WO2019204233A1 - Modulating immune response via targeting of olfactory receptor activity - Google Patents

Modulating immune response via targeting of olfactory receptor activity Download PDF

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Publication number
WO2019204233A1
WO2019204233A1 PCT/US2019/027558 US2019027558W WO2019204233A1 WO 2019204233 A1 WO2019204233 A1 WO 2019204233A1 US 2019027558 W US2019027558 W US 2019027558W WO 2019204233 A1 WO2019204233 A1 WO 2019204233A1
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olfr
agent
expression
cell
subject
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French (fr)
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Klaus Ley
Marco ORECCHIONI
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La Jolla Institute for Allergy and Immunology
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La Jolla Institute for Allergy and Immunology
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Priority to EP19788394.5A priority Critical patent/EP3781173A4/en
Priority to US17/048,059 priority patent/US20210145768A1/en
Priority to JP2020558506A priority patent/JP2021521248A/ja
Publication of WO2019204233A1 publication Critical patent/WO2019204233A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]

Definitions

  • the present invention identifies olfactory receptors in macrophages, monocytes and dendritic cells that can be targeted to modulate immune responses, including innate immune responses.
  • the olfactory receptors identified are present on macrophages (e.g. vascular macrophages) and their expression, activity, or binding can be targeted to modulate cardiovascular disease, atherosclerosis, infection, or cancer.
  • a method of modulating an immune response comprising modulating expression or activity of one or more olfactory receptors.
  • a method of modulating an adverse cardiovascular event or cardiovascular disease comprising modulating expression or activity of one or more olfactory receptors.
  • a method of modulating atherosclerosis comprising modulating expression or activity of one or more olfactory receptors.
  • the method comprises decreasing, reducing, inhibiting, suppressing, limiting or controlling expression or activity of one or more olfactory receptors. In other embodiments, the method comprises enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptors.
  • a method of modulating an immune response comprising modulating expression or activity of one or more olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7,
  • the one or more olfactory receptors includes Olfr2.
  • the method comprises decreasing, reducing, inhibiting, suppressing, limiting or controlling expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • the method comprises decreasing, reducing, inhibiting, suppressing, limiting or controlling expression or activity of one or more olfactory receptor listed in any of FIGs. 2A and 2B.
  • the method comprises enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • the method comprises enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptor listed in any of FIGs. 2A and 2B.
  • a method of decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation in a subject comprising modulating expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • a method of decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation in a subject comprising modulating expression or activity of one or more olfactory receptor listed in any of FIGs. 2A and 2B.
  • a method of decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject comprising modulating expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • a method of decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject comprising modulating expression or activity of one or more olfactory receptor listed in any of FIGs. 2 A and 2B.
  • the methods comprise decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, comprising modulating expression or activity of one or more olfactory receptors.
  • the methods comprise decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject, comprising modulating expression or activity of one or more olfactory receptors.
  • the method comprises one or more of reducing, inhibiting, suppressing, limiting, controlling, enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptors.
  • the reducing, inhibiting, suppressing, limiting, controlling, enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptors comprises reducing, inhibiting, suppressing, limiting, controlling, enhancing, stimulating, or inducing signaling through olfactory receptors and/or the respective downstream signaling effects of reducing, inhibiting, suppressing, limiting, controlling, enhancing, stimulating, inducing or increasing expression or activity of olfactory receptors.
  • Certain alternative embodiments comprise decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, or an adverse symptom of the autoimmune response, disorder or disease.
  • the one or more olfactory receptors are selected from the olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7,
  • the one or more olfactory receptors are selected from the olfactory receptors listed in any of FIGs. 2A and 2B. In some embodiments, the one or more olfactory receptors are selected from the olfactory receptors listed in any of FIGs. 2A and 2B. In some embodiments, the one or more olfactory receptors are selected from the olfactory receptors listed in any of FIGs. 2A and 2B. In some
  • such adverse symptoms of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an adverse symptom of the autoimmune response, disorder or disease include but are not limited to swelling, pain, rash, headache, fever, nausea, diarrhea, bloat, lethargy, skeletal joint stiffness or tissue or cell damage.
  • the adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or the adverse symptom of the autoimmune response, disorder or disease is chronic or acute.
  • the subject is in need of treatment for or is at risk of an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an autoimmune response, disorder or disease.
  • the immune disorder, inflammatory response, inflammation, autoimmune response disorder or autoimmune disease of the present methods include but are not limited rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis,
  • granulomatosis chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, stiff- man syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome or an allergy, Behcet's
  • T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome, T cell receptor deficiency, MHC class II deficiency, TAP-2 deficiency (MHC class I deficiency), ZAP70 tyrosine kinase deficiency and purine nucleotide phosphorylase (PNP) deficiency, antibody deficiencies, X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immuno
  • a method of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse cardiovascular event or cardiovascular disease comprising modulating expression or activity of one or more olfactory receptors.
  • the adverse cardiovascular event or cardiovascular disease includes but is not limited to coronary artery disease, peripheral artery disease, cerebrovascular disease, renal artery disease, stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma, atherosclerotic plaque formation or elevated blood cholesterol.
  • a method decreasing, reducing, inhibiting, suppressing, limiting or controlling atherosclerosis comprising modulating expression or activity of one or more olfactory receptors.
  • the one or more olfactory receptors are selected from the olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9. In some embodiments, the one or more olfactory receptors are selected from the olfactory receptors listed in any of FIGs. 2A and 2B.
  • a method of reducing or inhibiting in a subject a neoplasia, neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy, the method comprising modulating expression or activity of one or more olfactory receptors.
  • modulating expression or activity of one or more olfactory receptors comprises administering an agonist of one or more olfactory receptors.
  • increasing expression or activity of one or more olfactory receptors comprises administering an agonist of one or more olfactory receptors.
  • a method of reducing or inhibiting in a subject viral, bacterial or fungal infection comprising modulating expression or activity of one or more olfactory receptors.
  • these methods comprise one or more of reducing, inhibiting, suppressing, limiting, controlling enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptors.
  • the one or more olfactory receptors are selected from the olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • the one or more olfactory receptors are selected from the olfactory receptors listed in any of FIGs. 2A and 2B.
  • the agonist is one or more of the agonists listed in Table 8.
  • the methods comprise decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the neoplasia, neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy, or viral, bacterial or fungal infection.
  • the neoplasia, neoplastic disorder, tumor, cancer or malignancy of the methods provided herein include but are not limited to a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma; or a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pit
  • the methods comprise modulating an innate immune response in the subject.
  • the methods comprise modulating the activity of a macrophage.
  • the macrophage is a vascular macrophage.
  • a method for modulating expression or activity of one or more olfactory receptors comprising modulating the binding of the olfactory receptor to a ligand.
  • the modulating of the binding of the olfactory receptor to a ligand comprises inhibiting binding of the ligand to the olfactory receptor.
  • the modulating of the binding of the olfactory receptor to a ligand comprises agonizing binding of the ligand to the olfactory receptor.
  • the methods of the present invention comprise administering to the subject a therapeutically effective amount of an agent that modulates expression or activity of one or more olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • the methods of the present invention comprise administering to the subject a therapeutically effective amount of an agent that modulates expression or activity of one or more olfactory receptors listed in any of FIGs. 2A and 2B.
  • the agent is an antagonist or agonist of expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, and Table 9.
  • the antagonist or agonist is one or more of the agonists listed in Table 8 or the antagonists listed in Table 9.
  • the agent is an antagonist or agonist of expression or activity of one or more olfactory receptor listed in any of FIGs. 2A and 2B.
  • the agent is a protein, a peptide, an antibody, an siRNA, a small molecule or a ligand mimetic.
  • the subject is a mammal, including but not limited to a human.
  • a method of modulating an immune response in a subject comprising modulating expression or activity of one or more olfactory receptors (OLFR).
  • OLFR olfactory receptors
  • the OLFR is expressed by a cell in vivo.
  • the cell is an animal cell, with the proviso that the cell is not an olfactory cell.
  • the cell is a macrophage.
  • the macrophage is a vascular macrophage.
  • the modulation comprises one or more of inhibiting, decreasing, reducing, suppressing, limiting or controlling the immune response by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, or an adverse symptom of the autoimmune response, disorder or disease in the subject.
  • the adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an adverse symptom of the autoimmune response, disorder or disease is swelling, pain, rash, headache, fever, nausea, diarrhea, bloat, lethargy, skeletal joint stiffness or tissue or cell damage.
  • the adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or the adverse symptom of the autoimmune response, disorder or disease is chronic or acute.
  • immune disorder, inflammatory response, inflammation, autoimmune response disorder or autoimmune disease comprises rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis,
  • IBD inflammatory bowel disease
  • agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immunoglobulins; transient hypogammaglobulinemia of infancy, interferon g receptor (IFNGR1, IFNGR2) deficiency, interleukin 12 or interleukin 12 receptor deficiency, immunodeficiency with thymoma, Wiskott-Aldrich syndrome (WAS protein deficiency), ataxia telan
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse cardiovascular event or cardiovascular disease by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the adverse cardiovascular event or cardiovascular disease comprises coronary artery disease, peripheral artery disease, cerebrovascular disease, renal artery disease, stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma, atherosclerosis, atherosclerotic plaque formation or elevated blood cholesterol.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling atherosclerosis, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the method comprises one or more of reducing or inhibiting in a subject viral, bacterial or fungal infection, by a method comprising administering to the subject an effective amount of an agent that increases the expression of or activates the OLFR.
  • the modulation comprises one or more of comprising decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the neoplasia, neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy, or viral, bacterial or fungal infection by a method comprising administering to the subject an effective amount of an agent that increases the expression of or activates the OLFR.
  • the neoplasia, neoplastic disorder, tumor, cancer or malignancy treated is a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma; or a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid
  • the OLFR is an OLFR listed in any one of Tables 1-9, and FIGs. 2A and 2B. In some embodiments, the OLFR is an OLFR listed in Table 7. In some embodiments, the OLFR is selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the agent is selected from the group of: a ligand or small molecule that binds to the OLFR or blocks the binding of the OLFR to the ligand or an agent that inhibits the expression of the OLFR by the cell.
  • the agent is selected from the group of an antibody, fragment or mimetic that binds to OLFR or an OLFR ligand, an anti-OLFR gene silencing agent, octanal, heptanal, or a prodrug or solvate thereof.
  • the agent modulates the OLFR by modulating the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is a protein selected from the group of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), or guanine nucleotide binding protein G(olf) subunit alpha (Gnal).
  • the agent is a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the immune response is stimulated by a method comprising administering an agent that increases expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • a method of suppressing an immune response in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR), thereby suppressing an immune response in the subject.
  • OLFR olfactory receptor
  • the OLFR is an OLFR listed in any one of Tables 1-9. In some embodiments, the OLFR is an OLFR listed in Table 7. In some embodiments, the OLFR is selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the agent is a gene silencing agent. In some embodiments, the agent is a gene silencing agent.
  • the gene silencing agent is selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule is selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • the agent decreases the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the ligand is an OLFR ligand listed in Table 8.
  • the agent is an OLFR antagonist.
  • the OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • the OLFR antagonist is an antagonist listed in Table 9.
  • the agent decreases the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is an antibody, fragment or mimetic thereof that binds to an OLFR.
  • a method of suppressing an immune response in a subject in need thereof comprising administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby suppressing an immune response in the subject.
  • OLFR olfactory receptor
  • a method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of treating a cardiovascular disease in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of increasing an immune response in a subject in need thereof comprising administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby increasing an immune response in the subject.
  • OLFR olfactory receptor
  • a method of treating an infection in a subject in need thereof comprising administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of treating an infection in a subject in need thereof comprising administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • the infection is selected from the group consisting of a viral infection, bacterial infection, or fungal infection.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of modulating the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that modulates the expression or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • the agent increases the expression of or activates the OLFR.
  • the agent decreases the expression or activity of the OLFR.
  • a method of increasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of decreasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that decreases the expression of or inhibits an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of modulating the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that modulates the trafficking of an olfactory receptor (OLFR) to a plasma membrane of the cell.
  • OLFR olfactory receptor
  • the agent increases or promotes the trafficking of the OLFR to the plasma membrane of the cell.
  • the agent decreases or inhibits the trafficking of the OLFR to the plasma membrane of a cell.
  • a method of increasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of the cell.
  • OLFR olfactory receptor
  • a method of decreasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that decreases or inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • the methods comprise the use of one or more agents.
  • the agent is a gene silencing agent.
  • the gene silencing agent is selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator- like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator- like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule is selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • the agent decreases the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the ligand is an OLFR ligand listed in Table 8.
  • the agent is an OLFR antagonist.
  • the OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • the OLFR antagonist is an antagonist listed in Table 9.
  • the agent decreases the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is an antibody, fragment or mimetic thereof that binds to an OLFR.
  • the agent is an OLFR agonist.
  • the OLFR agonist is an agonist listed in Table 8.
  • the OLFR agonist is selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl- fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)- citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, ace
  • the agent is a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent comprises a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the OLFR is an OLFR listed in any one of Tables 1-9 and FIGs. 2A-2B. In some embodiments, the OLFR is an OLFR listed in Table 7. In some embodiments, the OLFR is selected from the group consisting of OR7C1, OR7D4,
  • the OLFR is expressed by a cell in vivo.
  • the cell is an animal cell, with the proviso that the cell is not an olfactory cell.
  • the cell is a macrophage.
  • the macrophage is a vascular macrophage.
  • the one or more proteins involved in an immune response is any of the proteins shown in FIGs. 16 and 17.
  • the one or more proteins involved in an immune response is a protein selected from CCL5 (C-C Motif Chemokine Ligand 5), Tnfrsfl2a (Osteoprotegerin), Axin 1, Nadk, Ahr (Aryl hydrocarbon receptor), QDPR (quinoid dihydropteridine reductase), HGF (Hepatocyte Growth Factor), ADAM23, or Snap29.
  • the administration is local or systemic. In some embodiments, the administration comprises by a method comprising intravenously.
  • the subject is a mammal. In some embodiments, the subject has or is predisposed to a disease or disorder involving an immune dysregulation. In some embodiments, the subject is a human patient.
  • kits comprising an agent that modulates the activity of an OLFR and instructions for use.
  • the agent is a gene silencing agent. In some embodiments, the agent is a gene silencing agent.
  • the gene silencing agent is selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule is selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • the agent modulates the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the ligand is an OLFR ligand listed in Table 8.
  • the agent is an OLFR antagonist.
  • the OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • the OLFR antagonist is an antagonist listed in Table 9.
  • the agent modulates the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is an antibody, fragment or mimetic thereof that binds to an OLFR.
  • the agent is an OLFR agonist.
  • the OLFR agonist is an agonist listed in Table 8.
  • the OLFR agonist is selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl- fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)- citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, ace
  • the agent is a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent comprises a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the OLFR is an OLFR listed in any one of Tables 1-9 and FIGs. 2A-2B.
  • the OLFR is an OLFR listed in Table 7.
  • the OLFR is selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • FIGs. 1A-C show a non-limiting example of Olfr2 inhibition with Citral and the resulting decrease in inflammatory gene expression and atherosclerosis progression in vivo.
  • FIG. 1A shows the results of a gene expression analysis of CCL2, CCL4, TNF and iNOS after treatment with the Olfr2 inhibitor citral alone or in combination with octanal and LPS.
  • FIG. IB shows the results of an atherosclerosis lesion evaluation (% and number of pixels with lesions) after the treatment with OLFR2 inhibitor citral.
  • FIG. 1C shows pictures of pinned aortas of mice treated with citral or saline (untreated).
  • FIG. 2A depicts a heat map of Olfr genes (total 1123) expressed in mouse vascular macrophages and several other tissue macrophages, DCs and blood monocytes.
  • FIG. 2B displays a heat map of expressed Olfrs with known human orthologues.
  • FIG. 3A shows the relative expression of Olfr2 quantified by real time PCR analysis of Olfr2 expression normalized to expression of Gapdh and untreated control.
  • FIG. 3B shows Olfr2 protein expression in BMDM lysate.
  • FIGs. 3C-D show flow cytometric analysis of extracellular Olfr2 expression. Median Fluorescence Intensity (MFI) of live F4/80 + BMDMs is reported.
  • MFI Median Fluorescence Intensity
  • FIG. 3F shows Olfr2 expression was determined by real-time PCR.
  • FIGs. 3G-H show flow cytometric analysis of 01fr2 by aortic macrophages.
  • FIG. 31 shows microphotographs depicting Olfr2, CD68 and Hoechst immunoreactivity in whole mount aorta from Apoe mouse fed WD for 2 weeks.
  • FIGs. 4A-B show Rtpl (FIG. 4A) and Rtp2 (FIG. 4B) expression in aorta as measured by qPCR.
  • FIGs. 5A-B show Olfr2 expression in T cells and B cells from whole digested aorta.
  • FIG. 6A show Olfr2 expression on blood mononuclear cells.
  • FIG. 6B shows Olfr2 function on blood mononuclear cells.
  • FIGs. 7A-G show that Olfr2 ligation induces an inflammatory response by vascular macrophages.
  • FIG. 7A Ca 2+ signals of Ctrl and Oct are displayed as a dot plot.
  • FIG. 7C Oct induces pro- inflammatory gene expression in aorta.
  • FIG. 7D Cit (100 mM) reduced octanal induced expression of Ccl2, Ccl4, Tnfi and Nos2 in aortas.
  • FIG. 7E CCL2, CCL4, and TNF protein quantification by cytokine bead arrays and flow cytometry in supernatants of stimulated aortas.
  • FIG. 7F Intracellular TNF expression in F4/80 + vascular endothelial cells
  • BMDMs were treated with LPS (50 ng/mL) for 18 h and subsequently stimulated with Oct and Cit alone or both combined.
  • FIGs. 8A-B show calcium (Ca2+) signal detection displayed as a dot plot.
  • FIG. 8A Dump channel-i- cells (TCRb+, and CD19+), loaded with 2mM Fluo-4 before and after addition of Olfr2 agonist octanal (Oct 10mM), and antagonist Citral (Cit IOOmM) alone or combined (Oct+Cit).
  • Oct, and Cit injected at 60 seconds.
  • Whole aortas were digested, stained with Fluo4 (2mM) at 37 °C for 30 min, then washed and incubated with cell surface markers at RT for 20 min.
  • FIG. 8B The time average Median Fluorescence Intensity (MFI) of Fluo-4 is reported. SD is calculated among the cells for each time point (n 20-50). The analysis is made out one of three experiments.
  • MFI Median Fluorescence Intensity
  • FIGs. 9A-B shows the results of evaluating octanal dose response.
  • RNA was quantified using a nanodrop spectrophotometer (Peqlab) and 500 ng were reverse transcribed into cDNA using Omniscript reverse transcriptase (Qiagen). Real time PCR reactions were performed according to the RT 2 SYBR green gene expression assay protocol (Qiagen). RT2 SYBR Green qPCR master mix and premade RT 2 qPCR Primer Assays for mouse Ccl2, Ccl4, and Gapdh were used. Relative expression was normalized to Gapdh expression and the untreated control. Data are presented as means ⁇ SEM. n 3 per group * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.005, **** p ⁇ 0.001.
  • FIGs. 10A-J shows that octanal concentration increases in blood plasma of western diet fed mice and exacerbates atherosclerosis.
  • FIGs. 10A-C Murine blood plasma was analyzed for octanal by derivatization and stable isotope dilution LC/MS/MS.
  • FIGS. 10D-G En face atherosclerosis quantification in vehicle-, octanal- or citral-treated mice.
  • D) Representative pictures of pinned aortic arches of vehicle and Oct-treated mice. Scale bar 0.5cm.
  • E) Enface atherosclerotic lesion size evaluation in aortic arches as percentage of total area analyzed.
  • FIGs. 11A-B shows body weight and hematological parameters, in octanal (FIG. 11A) and citral (FIG. 11B) treated mice.
  • NE Neutrophils
  • LY Lymphocytes
  • MO Monocytes
  • EO Eosinophils
  • BA Basophils
  • FIG. 12 shows body weight and hematological parameters, in Lldr-/- male mice (n 8/10 per group) transplanted with Ripl /Rip2+/+, Rtpl/Rtp2+/-, Rtpl/Rtp2-/- derived Bone Marrow cells and treated l2wks with high cholesterol diet.
  • FIG. 13 shows that human macrophages express the Olfr2 orthologue OR6A2 and ligation activates a pro-inflammatory response.
  • FIGS. 13B-E Monocytes from healthy human donors were differentiated into macrophages (hMDMs).
  • hMDMs were untreated or incubated with octanal (Oct, 10 mM) and LPS, (500 ng/mL) alone or combined (LPS+Oct) for 12 h.
  • Bi Quantitative real time PCR analysis of OR6A2 expression normalized to Gapdh expression and untreated control.
  • Bii and iii Flow cytometric analysis of OR6A2 expression on living hMDMs reported as MFI.
  • FIG. 13C High resolution imaging of hMDMs stained for OR6A2 (AF488) and hoechst dye (nuclei).
  • FIG. 13D Real time PCR quantification for human 1L6, TNF, and NOS2 gene expression normalized to Gapdh and untreated control.
  • FIG. 13F hMDMs were treated with LPS (50 ng/mL) for 18 h and left untreated or further incubated with Oct and Cit alone or combined. IL- 1 b protein in supernatants was quantified by a human cytokine bead array and flow cytometry.
  • FIG. 13G hMDMs were transfected with a OR6A2 small interfering RNAs (SiORA6A2) or scramble control siRNAs (SiCtrl).
  • hMDMs were treated with LPS (500 ng/mL) alone or with LPS+Oct (10 mM) for 12 h.
  • OR6A2 TNF, 1L6 and NOS2 gene expression analysis was analyzed by real time PCR and normalized to Gapdh and LPS siCtrl treated controls. All experiments were replicated at least three times. Data are presented as mean ⁇ SEM. * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.005, **** p ⁇ 0.001. p calculated by One-Way ANOVA test, Tukey's multiple comparisons test and unpaired t- test.
  • FIG. 14 shows an analysis of pro inflammatory genes CCL2, CCL4, and Tnf in aortas of Apoe ⁇ ⁇ mice.
  • Relative expression of Ccl2, Ccl4, and Tnf was quantified by real time PCR analysis and normalized to Gapdh expression and untreated control applying the 2-AACT method.
  • N 3 per group.
  • FIG. 15 shows a statistical analysis of the relative expression of pro
  • FIG. 16 shows significantly modulated proteins in plasma from octanal treated mice.
  • EDTA plasma samples were collected from octanal treated and vehicle treated mice at the end of the 8 weeks and were sent for analysis of 92 proteins.
  • Analysis of 92 proteins comprising the Olink Mouse exploratory panel (https://www.olink.com/products/mouse- exploratory/) was performed using PEA (Proximity Extension Assay) technology.
  • PEA Proximity Extension Assay
  • the PEA technique also permits accurate assessment of protein levels with repeated measurements by requiring both dual recognition of correctly matched antibody pairs and DNA-barcoding from sequence- specific oligonucleotides to generate a signal (PLoS ONE. 20l4;9(4)).
  • the assay measures fold change in log 2 units.
  • the raw data are converted into a t-statistic which can be compared across assays. Data are presented as means ⁇ SEM. P value ⁇ 0.05 calculated by unpaired t-test.
  • FIG. 17 shows significantly modulated proteins in plasma from citral treated mice.
  • EDTA plasma samples were collected from citral treated and vehicle treated mice at the end of the 8 weeks and were sent for analysis of 92 proteins.
  • Analysis of 92 proteins comprising the Olink Mouse exploratory panel (https://www.olink.com/products/mouse- exploratory/) was performed using PEA (Proximity Extension Assay) technology, discussed above. Data are presented as means ⁇ SEM. P value ⁇ 0.05. p calculated by unpaired t-test.
  • Olfrs olfactory receptors
  • RTP1 Receptor Transporter Protein 1
  • RTP2 Receptor Transporter Protein 2
  • octanal stimulation of the olfactory receptor Olfr2 by a small molecule odorant (octanal) induces expression of inflammatory mediators, CCL2 (C-C motif chemokine ligand 2), iNOS (inducible Nitric Oxide Synthase) and TNF (tumor necrosis factor alpha); exposure to both octanal and LPS (lipopolysaccharide) exacerbate the inflammatory response, indicating that the inflammation may be caused by microbiota-derived odorants.
  • CCL2 C-C motif chemokine ligand 2
  • iNOS inducible Nitric Oxide Synthase
  • TNF tumor necrosis factor alpha
  • Olfactory receptors are class A, G protein coupled receptors (GPCRs) that are bound by volatile chemical ligands, or odorants. Olfrs were first described in olfactory epithelial cells in the nasal cavity of rats 1 2 . Olfrs have an average length of 320+25 amino acid residues and share characteristic conserved motifs 3 . Olfr genes constitute the largest family GPCRs with -1100 genes in mice and -400 in humans 4,5 . Many Olfrs require the transporters Rtpl and 2 and other molecules such as receptor expression enhancing protein 3 (Reep3) for expression 6 .
  • Reep3 receptor expression enhancing protein 3
  • Activation of Ga(olf) and Acy3 induces an increase in the intracellular concentration of cyclic adenosine monophosphate (cAMP) followed by the activation of cAMP-gated channels, influx of extracellular Na + and Ca 2+ , and membrane depolarization.
  • cAMP cyclic adenosine monophosphate
  • Olfr2 ligand octanal significantly enhances LPS-induced inflammatory cytokines, which is blocked by the Olfr2 antagonist citral.
  • Octanal naturally occurred in citrus oils and is used as a flavor food additive. It is in a class of odorants (aldheydes) that may have effects on atherosclerosis. Treating Apoe-/- mice with citral reduced their atherosclerotic lesions by -50%.
  • Olfr2 is highly expressed in vascular macrophage. qRT-PCR showed that Olfr2 expression is increased fourfold by LPS and further increased by adding its ligand octanal, but octanal alone had no effect on Olfr2 expression.
  • Olfr2 This increased expression of Olfr2 was confirmed at the protein level. Without being bound by theory, Applicants believe that it may be caused by increased expression of the transporters Rpt 1 and 2, which are both induced by LPS. LPS treatment of mice also increased Olfr2 expression on Ly6C+ blood monocytes and, to a lesser extent, on Ly6C- patrolling monocytes, but not on any other immune cells in the aorta or in blood (data not shown).
  • inflammatory cytokines, chemokines and the Ml -defining enzyme iNOS were surveyed by qRT-PCR.
  • iNOS expression induced by LPS was greatly enhanced by octanal.
  • Octanal had the greatest effect on TNF, where ligation of Olfr2 was required to reveal an LPS-induced increase.
  • the enhanced production of CCL2, CCL4 and TNF was confirmed at the protein level by cytometric bead array. Octanal also boosted the expression of TNF in both Ly6C+ and Ly6C- blood monocytes.
  • TMAO microbiota-derived molecules are known to promote atherosclerosis, e.g., TMAO.
  • TMAO is produced by intestinal bacteria from choline. It has various effects, including enhanced platelet activation.
  • Other microbiota-derived odorants have been identified.
  • some of the identified microbiota-derived odorants include TMA and its liver derivative TMAO, p-cresol and its liver derivatives p-cresol-sulfate and p-cresol-glucuronide, indole and its liver derivatives indoxyl- sulfate and indoxyl-glucuronide, tryptamine, serotonin (also endogenous), SCFA (acetic, propionic, butyric, valeric, isovaleric, succinic, lactic acid), Phenylacetic acid and its liver derivatives phenylacetyl- glutamine and phenylacetyl-glycine, Indole-acetic acid, Indole-propionic acid, Phenyl-acetic acid, Phenyl-propionic acid, Benzoic acid and its liver derivative hippuric acid (also 2-hydroxy benzoic, 3-hydroxy benzoic and 4-hydroxybenzoic and their liver derivatives).
  • TMAO TMAO
  • the olfactory receptors identified herein are modulated for treatment of an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an autoimmune response, disorder or disease including but not limited to rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis
  • IBD inflammatory bowel disease
  • IBD cutaneous lupus erythematosus
  • granulomatosis chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, stiff- man syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome or an allergy, Behcet's
  • T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome, T cell receptor deficiency, MHC class II deficiency, TAP-2 deficiency (MHC class I deficiency), ZAP70 tyrosine kinase deficiency and purine nucleotide phosphorylase (PNP) deficiency, antibody deficiencies, X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immuno
  • the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an autoimmune response, disorder or disease is a symptom, side-effect or result of is of cancer or a pathogen infection.
  • the olfactory receptors identified herein are modulated for treatment of a neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • the present invention comprises modulating one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6,
  • the present invention comprises decreasing, reducing, inhibiting, suppressing, limiting or controlling expression or activity of one or more olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIGs. 2A and 2B.
  • the present invention comprises enhancing, stimulating, inducing or increasing expression or activity of one or more olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIGs. 2A and 2B.
  • the present invention comprises a combination of decreasing, reducing, inhibiting, suppressing, limiting or controlling expression or activity of one or olfactory receptors listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIGs. 2A and 2B, and enhancing, stimulating, inducing or increasing expression or activity of one or more different olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIGs. 2A and 2B.
  • Non- limiting examples of an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or an autoimmune response, disorder or disease include rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis,
  • IBD inflammatory bowel disease
  • granulomatosis chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, stiff- man syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome or an allergy, Behcet's
  • T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome, T cell receptor deficiency, MHC class II deficiency, TAP-2 deficiency (MHC class I deficiency), ZAP70 tyrosine kinase deficiency and purine nucleotide phosphorylase (PNP) deficiency, antibody deficiencies, X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immuno
  • Non-limiting examples of neoplasia, neoplastic disorders, tumors, cancers or malignancies treated by the present methods include, a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma as well as a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast
  • the method of modulating an immune response in a subject comprises modulating expression or activity of one or more olfactory receptors (OLFR).
  • OLFR olfactory receptors
  • the OLFR may be expressed by a cell in vivo.
  • the cell may be an animal cell, with the proviso that the cell is not an olfactory cell.
  • the cell may be a macrophage.
  • the macrophage may be a vascular macrophage.
  • the modulation may comprise one or more of inhibiting, decreasing, reducing, suppressing, limiting or controlling the immune response by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the (OLFR).
  • the modulation may comprise one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the (OLFR).
  • the modulation may comprise one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the (OLFR).
  • the modulation may comprise one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, or an adverse symptom of the autoimmune response, disorder or disease in the subject.
  • the methods or uses disclosed herein may comprise modulating an adverse symptom.
  • autoimmune response, disorder or disease may be swelling, pain, rash, headache, fever, nausea, diarrhea, bloat, lethargy, skeletal joint stiffness or tissue or cell damage.
  • the adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation or the adverse symptom of the autoimmune response, disorder or disease may be chronic or acute.
  • the immune disorder, inflammatory response, inflammation, autoimmune response disorder or autoimmune disease may comprise rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrot
  • thrombocytopenia polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, stiff-man syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing va
  • agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immunoglobulins; transient hypogammaglobulinemia of infancy, interferon g receptor (IFNGR1, IFNGR2) deficiency, interleukin 12 or interleukin 12 receptor deficiency, immunodeficiency with thymoma, Wiskott-Aldrich syndrome (WAS protein deficiency), ataxia telan
  • the modulation may comprise one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse cardiovascular event or cardiovascular disease by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the adverse cardiovascular event or cardiovascular disease may comprise coronary artery disease, peripheral artery disease, cerebrovascular disease, renal artery disease, stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma, atherosclerosis, atherosclerotic plaque formation or elevated blood cholesterol.
  • the modulation may comprise one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling atherosclerosis, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the method may comprise one or more of reducing or inhibiting in a subject viral, bacterial or fungal infection or a neoplasia, neoplastic disorder, tumor, cancer or malignancy, by a method comprising administering to the subject an effective amount of an agent that increases the expression of or activates the OLFR.
  • the modulation may comprise one or more of comprising decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the neoplasia, neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy, or viral, bacterial or fimgal infection by a method comprising administering to the subject an effective amount of an agent that modulates the expression of or activity of the OLFR.
  • the OLFR may be enhanced or stimulated in the subject by administration of an effective amount of an agent that stimulates or enhances the activity of the OLFR.
  • the OLFR may be enhanced or stimulated in the subject by administration of an OLFR.
  • the OLFR may be enhanced or stimulated in the subject by administration of a nucleotide that encodes an OLFR.
  • the OLFR may be enhanced or stimulated in the subject by
  • the OLFR may be enhanced or stimulated in the subject by administration of a receptor transporting protein 1 (RTP1) or a nucleotide encoding RTP1.
  • RTP1 receptor transporting protein 1
  • the OLFR may be enhanced or stimulated in the subject by administration of a RTP2 or a nucleotide encoding RTP2.
  • REEP1 receptor expression enhancing protein 1
  • the OLFR may be enhanced or stimulated in the subject by administration of an aminoacylase 3 (Acy3) or a nucleotide encoding Acy3.
  • the OLFR may be enhanced or stimulated in the subject by administration of a guanine nucleotide-binding protein G(olf) subunit alpha (Gnal) or a nucleotide encoding Gnal.
  • the methods disclosed herein may be used to treat a neoplasia, neoplastic disorder, tumor, cancer or malignancy. Further disclosed herein is the use of an agent that modulates the activity or expression of an OLFR in the preparation of a medicament for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy. Further disclosed herein is the use of an agent that increases the activity or expression of an OLFR in the preparation of a medicament for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • an OLFR ligand in the preparation of a medicament for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • octanal in the preparation of a medicament for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • an OLFR ligand for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • octanal for the treatment of a neoplasia, neoplastic disorder, tumor, cancer or malignancy.
  • the neoplasia, neoplastic disorder, tumor, cancer or malignancy treated may be a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma; or a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland, thyroid
  • the methods and uses disclosed herein may comprise modulating the activity or expression of an OLFR.
  • the OLFR may be an OLFR listed in any one of Tables 1-9 Tables 2 A and 2B.
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be selected from the group of: a ligand or small molecule that binds to the OLFR or blocks the binding of the OLFR to the ligand or an agent that inhibits the expression of the OLFR by the cell.
  • the agent may be a ligand or small molecule that binds to the OLFR.
  • the agent may be a ligand or small molecule that blocks the binding of the OLFR to the ligand.
  • the agent may inhibit the expression of the OLFR by the cell.
  • the agent may be selected from the group of an antibody, fragment or mimetic that binds to OLFR or an OLFR ligand, an anti-OLFR gene silencing agent, or octanal or a prodrug or solvate thereof.
  • the agent may be an antibody, fragment or mimetic that binds to OLFR.
  • the agent may be an antibody, fragment or mimetic that binds to an OLFR ligand.
  • the agent may be an anti-OLFR gene silencing agent.
  • the agent may be octanal, heptanal, or a prodrug or solvate thereof.
  • the agent may activate the OLFR by increasing the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be a protein selected from the group of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), or guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may be a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the immune response may be stimulated by a method comprising administering an agent that increases expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), interleukin l-beta (IL-1B), interleukin 18 (IL-18), and nitric oxide synthase 2 (NOS2).
  • TNF tumor necrosis factor
  • CCL2 C-C motif chemokine ligand 2
  • CCL4 CCL5
  • IL-6 interleukin 6
  • IL-1B interleukin l-beta
  • IL-18 interleukin 18
  • NOS2 nitric oxide synthase 2
  • the inflammatory cytokine may be TNF.
  • the inflammatory cytokine may be CCL2.
  • the inflammatory cytokine may be CCL4.
  • the inflammatory cytokine may be CCL5.
  • the inflammatory cytokine may be IL-6.
  • the inflammatory cytokine may be IL-1B.
  • the inflammatory cytokine may be IL-18.
  • the inflammatory cytokine may be NOS2.
  • the method comprises administering to the subject an olfactory receptor (OLFR).
  • the method comprises administering to the subject an agent that increases the expression of or activity of an olfactory receptor (OLFR), thereby increasing or stimulating an immune response in the subject.
  • the method comprises administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby increasing an immune response in the subject.
  • an olfactory receptor (OLFR) in the manufacture of a medicament for increasing or stimulating an immune response.
  • an agent that increases the expression of or activity of an olfactory receptor (OLFR) in the manufacture of a medicament for increasing or stimulating an immune response is disclosed herein.
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG. 2 A.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10HL
  • the OLFR may be OR6A2.
  • the agent may be a ligand that binds to the OLFR.
  • the agent may be an OLFR agonist.
  • the agonist may be selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3- phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl- fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)-citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, acetophenone, amyl butyrate, nonanethiol, allyl phenyl acetate, N-amyl acetate, muscone, iso
  • the agent may be octanal, heptanal, or a prodrug or solvate thereof.
  • the agent may activate the OLFR by increasing the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may comprise a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • Stimulating an immune response may comprise increasing expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • the immune response is increased or stimulated by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 100% as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be increased or stimulated by at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be increased or stimulated by at least 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or lOO-fold or more as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be measured by detecting the level of one or more inflammatory cytokines.
  • the immune response is measured by detecting the expression of one or more inflammatory cytokines.
  • the immune response is measured by detecting one or more circulating cytokines and/or chemokines.
  • the immune response is measured by detecting one or more cells selected from activated CD8 T cells, Thl cells, Th2 cells, Thl7 cells, TFH cells, TIP-DCs, and Ml polarized macrophages. In some embodiments, the immune response is measured by detecting one or more markers of T cell activation. In some embodiments, the immune response is measured by detecting the levels of antibody titers to one or more tumor antigens. In some embodiments, an increase in the expression level of or more
  • inflammatory cytokines is indicative of an increase in the immune response.
  • an increase in the quantity of circulating cytokines and/or chemokines is indicative of an increase in the immune response.
  • an increase in the quantity of one or more cells is indicative of an increase in the immune response.
  • an increase in quantity of one or more markers of T cell activation that is detected is indicative of an increase in the immune response.
  • an increase in the level of antibody titers detected is indicative of an increase in the immune response.
  • the immune response is measured by a method such as ELISA, cytometric bead array, Olink proteomic, and flow cytometry.
  • the method comprises administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR), thereby suppressing an immune response in the subject.
  • the method comprises administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby suppressing an immune response in the subject.
  • OLFR olfactory receptor
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG. 2A.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be a gene silencing agent.
  • the gene silencing agent may be selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule may be selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and micro RNA
  • the agent may decrease the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the agent may be an OLFR antagonist.
  • the OLFR antagonist may be citral, a solvate or prodrug thereof.
  • the OLFR antagonist may be methylcinnamaldehyde, hydrocinnamaldehyde, bourgeonal, undecanal, methyl isoeugenol a solvate or prodrug thereof.
  • the antagonist may be selected from the list of antagonists provided in Table 8, or a solvate or prodrug thereof.
  • the agent may decrease the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be an antibody, fragment or mimetic thereof that binds to an OLFR.
  • the immune response is suppressed or decreased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 100% as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be suppressed or decreased by at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be suppressed or decreased by at least 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or lOO-fold or more as compared to the immune response in a subject who is not treated with the agent.
  • the immune response may be measured by detecting the level of one or more inflammatory cytokines. Alternatively, or additionally, the immune response is measured by detecting the expression of one or more inflammatory cytokines. In some embodiments, the immune response is measured by detecting one or more circulating cytokines and/or chemokines.
  • the immune response is measured by detecting one or more cells selected from activated CD8 T cells, Thl cells, Th2 cells, Thl7 cells, TFH cells, TIP-DCs, and Ml polarized macrophages. In some embodiments, the immune response is measured by detecting one or more markers of T cell activation. In some embodiments, the immune response is measured by detecting the levels of antibody titers to one or more tumor antigens. In some embodiments, a decrease in the expression level of or more inflammatory cytokines is indicative of a decrease or suppression in the immune response. In some embodiments, a decrease in the quantity of circulating cytokines and/or chemokines is indicative of a decrease or suppression in the immune response.
  • a decrease in the quantity of one or more cells is indicative of a decrease or suppression in the immune response.
  • a decrease in quantity of one or more markers of T cell activation that is detected is indicative of a decrease or suppression in the immune response.
  • a decrease in the level of antibody titers detected is indicative of a decrease or suppression in the immune response.
  • the immune response is measured by a method such as ELISA, cytometric bead array, Olink proteomic, and flow cytometry.
  • the method comprises administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • the method of treating an autoimmune disease in a subject in need thereof comprises administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • an agent that decreases the expression of or activity of an olfactory receptor (OLFR) in the manufacture of a medicament for treating an autoimmune disease is also disclosed herein is the use of an agent that decreases the expression of or activity of an olfactory receptor (OLFR) for the treatment of an autoimmune disease.
  • OLFR olfactory receptor
  • OLFR olfactory receptor
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG. 2 A.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1,
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be a gene silencing agent.
  • the gene silencing agent may be selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule may be selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • the agent may decrease the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the agent may be an OLFR antagonist.
  • the OLFR antagonist may be citral, a solvate or prodrug thereof.
  • the OLFR antagonist may be methylcinnamaldehyde, hydrocinnamaldehyde, bourgeonal, undecanal, methyl isoeugenol a solvate or prodrug thereof.
  • the antagonist may be selected from the list of antagonists provided in Table 9, or a solvate or prodrug thereof.
  • the agent may decrease the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be an antibody, fragment or mimetic thereof that binds to an OLFR.
  • the autoimmune disease is selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, inflammatory bowel disease (IBD), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemor
  • IBD inflammatory bowel
  • granulomatosis chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis, Hashimoto's thyroiditis, autoimmune polyglandular syndrome, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, immune-mediated infertility, autoimmune Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, Guillain-Barre syndrome, stiff- man syndrome, acute rheumatic fever, sympathetic ophthalmia, Goodpasture's syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome or an allergy, Behcet's
  • T cell immunodeficiency such as DiGeorge syndrome, Nude syndrome, T cell receptor deficiency, MHC class II deficiency, TAP-2 deficiency (MHC class I deficiency), ZAP70 tyrosine kinase deficiency and purine nucleotide phosphorylase (PNP) deficiency, antibody deficiencies, X-linked agammaglobulinemia (Bruton's tyrosine kinase deficiency), autosomal recessive agammaglobulinemia, Mu heavy chain deficiency, surrogate light chain (g5/l4.l) deficiency, Hyper-IgM syndrome: X-linked (CD40 ligand deficiency) or non-X-linked, Ig heavy chain gene deletion, IgA deficiency, deficiency of IgG subclasses (with or without IgA deficiency), common variable immunodeficiency (CVID), antibody deficiency with normal immuno
  • the method comprises administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • the method comprises administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • cardiovascular disease Also disclosed herein is the use of an agent that decreases the expression of or activity of an olfactory receptor (OLFR) for the treatment of a
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG. 2A.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be a gene silencing agent.
  • the gene silencing agent may be selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • the RNAi molecule may be selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • the agent may decrease the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the agent may be an OLFR antagonist.
  • the OLFR antagonist may be citral, a solvate or prodrug thereof.
  • the OLFR antagonist may be methylcinnamaldehyde, hydrocinnamaldehyde, bourgeonal, undecanal, methyl isoeugenol a solvate or prodrug thereof.
  • the antagonist may be selected from the list of antagonists provided in Table 9 or a solvate or prodrug thereof.
  • the agent may decrease the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be an antibody, fragment or mimetic thereof that binds to an OLFR.
  • the adverse cardiovascular event or cardiovascular disease is selected from the group consisting of coronary artery disease, peripheral artery disease, cerebrovascular disease, renal artery disease, stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma, atherosclerosis, atherosclerotic plaque formation and elevated blood cholesterol.
  • the method comprises administering to the subject an olfactory receptor (OLFR).
  • the method comprises administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • the method comprises administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • an olfactory receptor (OLFR) in the manufacture of a medicament for the treatment of an infection.
  • an agent that increases the expression of or activates an olfactory receptor (OLFR) in the manufacture of a medicament for the treatment of an infection is disclosed herein.
  • an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell in the manufacture of a medicament for the treatment of an infection is disclosed herein.
  • an olfactory receptor (OLFR) for the treatment of an infection or infectious disease.
  • an agent that increases the expression of or activates an olfactory receptor (OLFR) for the treatment of an infection or infectious disease is disclosed herein.
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be a ligand that binds to the OLFR.
  • the agent may be an OLFR agonist.
  • the agonist may be selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl- fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)- citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, acetophenone, amyl butyrate, nonanethiol, allyl phenyl acetate, N-amyl acetate, muscone, is
  • the agonist may be selected from the list of agonists provided in Table 8.
  • the agent may be octanal, heptanal, or a prodrug or solvate thereof.
  • the agent may activate the OLFR by increasing the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may comprise a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • Stimulating an immune response may comprise increasing expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • TNF tumor necrosis factor
  • CCL2 C-C motif chemokine ligand 2
  • CCL4 C-C motif chemokine ligand 2
  • IL-6 interleukin 6
  • the infection is a viral infection.
  • the viral infection is caused by a virus selected from the group consisting of influenza virus, enterovirus (such as coxsackievirus and echovirus), cytomegalovirus, Zika virus, rabies virus, West Nile virus, rubella virus, polio virus, rotavirus, norovirus, herpes simplex virus, varicella- zoster virus, lymphocytic choriomeningitis virus, human immunodeficiency virus, Chikungunya virus, Crimean-Congo hemorrhagic fever virus, Japanese encephalitis virus, Rift Valley Fever virus, Ross River virus, and louping ill virus.
  • enterovirus such as coxsackievirus and echovirus
  • cytomegalovirus Zika virus
  • rabies virus West Nile virus
  • rubella virus rubella virus
  • polio virus polio virus
  • rotavirus norovirus
  • herpes simplex virus varicella- zoster virus
  • the infection is a bacterial infection. In some embodiments, the infection is a bacterial infection.
  • the bacterial infection is caused by a bacteria selected from the group consisting of streptococcus, staphylococcus, Escherichia coli, Campylobacter jejuni, Clostridium botulinum, listeria monocytogenes, salmonella, and vibrio.
  • the infection is a fungal infection.
  • the fungal infection is caused by a fungus selected from the group consisting aspergillus, Candida, coccidioides, sphorotrichosis, Pneumocystis jirovecii, Blastomyces, Histoplasma, Cryptococcus neoformans, and Talaromyces.
  • fungal infections include, but are not limited to aspergillosis, candidiasis, C.
  • gattii infection fungal nail infection, mucormycosis, pneumocystis pneumonia, blastomycosis, sporotrichosis, histoplasmosis, mycetoma, ringworm, talaromycosis, athlete’s foot and yeast infection.
  • the infection is selected from the group consisting of a respiratory infection, gastrointestinal infection, liver infection, nervous system infection, ear infection, throat infection, bladder infection, kidney infection, urinary tract infection, sexually transmitted diseases, and skin infection.
  • the infection is a respiratory infection.
  • respiratory infections include, but are not limited to, sore throat, bronchitis, sinusitis, tuberculosis, and pneumonia.
  • the infection is a sexually transmitted disease.
  • sexually transmitted diseases include, but are not limited to, chlamydia, gonorrhea, syphilis, and bacterial vaginosis.
  • the infection is a skin infection.
  • skin infections include, but are not limited to, cellulitis, folliculitis, impetigo, and boils.
  • the method comprises administering to the subject an olfactory receptor (OLFR).
  • the method comprises administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • the method comprises administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • an agent that increases the expression of or activates an olfactory receptor (OLFR) in the manufacture of a medicament for the treatment of cancer.
  • an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell in the manufacture of a medicament for the treatment of cancer Disclosed herein is the use of an agent that increases the expression of or activates an olfactory receptor (OLFR) for the treatment of cancer.
  • the OLFR may be an OLFR listed in Table 1.
  • the OLFR may be an OLFR listed in Table 2.
  • the OLFR may be an OLFR listed in Table 3.
  • the OLFR may be an OLFR listed in Table 4.
  • the OLFR may be an OLFR listed in Table 5.
  • the OLFR may be an OLFR listed in Table 6.
  • the OLFR may be an OLFR listed in Table 7.
  • the OLFR may be an OLFR listed in Table 8.
  • the OLFR may be an OLFR listed in Table 9.
  • the OLFR may be an OLFR listed in FIG. 2A.
  • the OLFR may be an OLFR listed in FIG. 2B.
  • the OLFR may be selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the OLFR may be OR7C1.
  • the OLFR may be OR7D4.
  • the OLFR may be OR10A6.
  • the OLFR may be OR11H6.
  • the OLFR may be OR4E2.
  • the OLFR may be OR10H1.
  • the OLFR may be OR6A2.
  • the agent may be a ligand that binds to the OLFR.
  • the agent may be an OLFR agonist.
  • the agonist may be selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl- fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)- citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, acetophenone, amyl butyrate, nonanethiol, allyl phenyl acetate, N-amyl acetate, muscone, is
  • the agonist may be selected from the list of agonists provided in Table 8.
  • the agent may be octanal, heptanal, or a prodrug or solvate thereof.
  • the agent may activate the OLFR by increasing the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent may be a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may comprise a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • Stimulating an immune response may comprise increasing expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5 interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • the administration may be local.
  • the administration may be systemic.
  • the administration may comprise an intravenous method.
  • the subject may be a mammal.
  • the subject may have or may be predisposed to a disease or disorder involving an immune dysregulation.
  • the subject may be a human patient.
  • the neoplasia, neoplastic disorder, tumor, cancer or malignancy treated is selected from the group consisting of a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma; or a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast
  • An“agent” as used herein refers to any molecule (e.g. antibody, Fab fragment, protein, peptide, nucleic acid, synthetic chemical, small chemical molecule, ligand mimetic) that can be administered to a subject.
  • An agent that modulates expression or activity of an olfactory receptor provided in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIG. 2A, and FIG. 2B is a molecule or composition that when administered to a subject modulates expression or activity of an olfactory receptor provided in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIG. 2A, and FIG. 2B.
  • the agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits expression or activity of an olfactory receptor provided in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIG. 2A, and FIG. 2B.
  • the agent modulates, enhances, stimulates, induces or increases expression or activity of an olfactory receptor provided in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIG. 2A, and FIG. 2B.
  • the agent modulates, inhibits, blocks, decreases, increases, enhances, promotes or elicits an immune response.
  • the agent modulates, enhances, stimulates, induces or increases an immune response.
  • modulation of an immune response includes modulating the innate immune response (e.g. endothelial cells, macrophages, monocytes, dendritic cells, cytokines).
  • the methods, uses, and kits disclosed herein may comprise one or more agents that modulate the activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • the agent may be selected from the group of: a ligand or small molecule that binds to the OLFR or blocks the binding of the OLFR to the ligand or an agent that inhibits the expression of the OLFR by the cell.
  • the agent may be selected from the group of an antibody, fragment or mimetic that binds to OLFR or an OLFR ligand, an anti-OLFR gene silencing agent, or octanal or a prodrug or solvate thereof.
  • the methods, uses, and kits disclosed herein may comprise one or more agents that increase the expression of or activity of an OLFR.
  • the agent may be a ligand that binds to an OLFR listed in any one of Tables 1-9 and FIGs. 2A-2B.
  • the agent may be a ligand that binds to an OLFR listed in Table 7.
  • the agent may be a ligand that binds to an OLFR selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the agent may be octanal, heptanal, or a prodrug or solvate thereof.
  • the expression of the OLFR is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
  • the expression of the OLFR is increased by at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more.
  • the activity of the OLFR is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100% or more.
  • the activity of the OLFR is increased by at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4, 5.5, 6, 6.5, 7, 7.5, 8, 8.5,
  • the activity of the OLFR is determined by measuring the level of expression of one or more inflammatory cytokines. In some embodiments, the activity of the OLFR is determined by measuring the level of secretion of one or more inflammatory cytokines. In some embodiments, the increase in the expression of OLFR is based on a comparison to the subject who has not been administered the agent. Alternatively, or additionally, the expression of the OLFR is measured over a time period and the increase in the level of expression of the OLFR is based on a comparison of samples from the subject over two or more time points.
  • the increase in the activity of OLFR is based on a comparison to the subject who has not been administered the agent.
  • the activity of the OLFR is measured over a time period and the increase in the activity of the OLFR is based on a comparison of samples from the subject over two or more time points.
  • the methods, uses, and kits disclosed herein may comprise one or more agents that increase or promote the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • the agent may be a protein selected from the group of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), or guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may comprise a nucleotide encoding a protein selected from the group of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), or guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • G(olf) subunit alpha Gnal
  • the level of trafficking of the OLFR to the plasma membrane is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100% or more.
  • the level of trafficking of the OLFR to the plasma membrane is increased by at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more.
  • the level of trafficking of the OLFR to the plasma membrane is determined by detecting the amount of OLFR on the surface of the cell.
  • the increase in the level of trafficking of the OLFR to the plasma membrane is based on a comparison to the subject who has not been administered the agent.
  • the level of trafficking of the OLFR to the plasma membrane is measured over a time period and the increase in the level of trafficking is based on a comparison of samples from the subject over two or more time points.
  • the methods, uses, and kits disclosed herein may comprise one or more agents that increase expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • the methods, uses, and kits disclosed herein may comprise one or more agents that decrease or inhibit the expression of or activity of an OLFR.
  • the agent may be a gene silencing agent.
  • the gene silencing agent may be selected from the group consisting of a RNA interference (RNAi) molecule, zinc finger nuclease, transcription activator-like effector nuclease (TALEN), and Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) enzyme.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • the RNAi molecule may be selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and micro RNA
  • the gene silencing agent may target an OLFR listed in any one of Tables 1-9 and FIGs. 2A-2B.
  • the gene silencing agent may target an OLFR listed in Table 7.
  • the gene silencing agent may target an OLFR selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the expression of the OLFR is decreased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100% or more.
  • the expression of the OLFR is decreased by at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more.
  • the activity of the OLFR is decreased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 100% or more.
  • the activity of the OLFR is decreased by at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 4, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or lO-fold or more.
  • the activity of the OLFR is determined by measuring the level of expression of one or more inflammatory cytokines.
  • the activity of the OLFR is determined by measuring the level of secretion of one or more inflammatory cytokines.
  • the decrease in the expression of OLFR is based on a comparison to the subject who has not been administered the agent.
  • the expression of the OLFR is measured over a time period and the decrease in the level of expression of the OLFR is based on a comparison of samples from the subject over two or more time points.
  • the decrease in the activity of OLFR is based on a comparison to the subject who has not been administered the agent.
  • the activity of the OLFR is measured over a time period and the decrease in the activity of the OLFR is based on a comparison of samples from the subject over two or more time points.
  • RNA interference RNA interference
  • CRISPR CRISPR
  • TALEN TALEN
  • ZFN RNA interference
  • CRISPR, TALEN, ZFN or other genome editing tools can also be used to modulate expression and/or function of genes.
  • RNAi refers to the method of reducing or eliminating gene expression in a cell by targeting specific mRNA sequences for degradation via introduction of short pieces of double stranded RNA (dsRNA) and small interfering RNA (such as siRNA, shRNA or miRNA etc.) (Agrawal, N. et a ; Microbiol Mol Biol Rev. 2003; 67:657-685, Arenz, C. et ak; Naturwissenschaften. 2003; 90:345-359, Hannon GL; Nature. 2002; 418:244-251).
  • dsRNA double stranded RNA
  • small interfering RNA such as siRNA, shRNA or miRNA etc.
  • CRISPR refers to a technique of sequence specific genetic manipulation relying on the clustered regularly interspaced short palindromic repeats pathway. CRISPR can be used to perform gene editing and/or gene regulation, as well as to simply target proteins to a specific genomic location.
  • Gene editing refers to a type of genetic engineering in which the nucleotide sequence of a target polynucleotide is changed through introduction of deletions, insertions, single stranded or double stranded breaks, or base substitutions to the polynucleotide sequence.
  • CRISPR- mediated gene editing utilizes the pathways of non-homologous end-joining (NHEJ) or homologous recombination to perform the edits.
  • NHEJ non-homologous end-joining
  • Gene regulation refers to increasing or decreasing the production of specific gene products such as protein or RNA.
  • gRNA or“guide RNA” as used herein refers to guide RNA sequences used to target specific polynucleotide sequences for gene editing employing the CRISPR technique.
  • Techniques of designing gRNAs and donor therapeutic polynucleotides for target specificity are well known in the art. For example, Doench, J., et al. Nature biotechnology 2014; 32(l2):l262-7, Mohr, S. et al. (2016) FEBS Journal 283: 3232-38, and Graham, D., et al. Genome Biol. 2015; 16: 260.
  • gRNA comprises or alternatively consists essentially of, or yet further consists of a fusion polynucleotide comprising CRISPR RNA (crRNA) and trans-activating CRIPSPR RNA (tracrRNA); or a polynucleotide comprising CRISPR RNA (crRNA) and trans-activating CRIPSPR RNA (tracrRNA).
  • a gRNA is synthetic (Kelley, M. et al. (2016) J of Biotechnology 233 (2016) 74-83).
  • Cas9 refers to a CRISPR associated endonuclease referred to by this name.
  • Non-limiting exemplary Cas9s include Staphylococcus aureus Cas9, nuclease dead Cas9, and orthologs and biological equivalents each thereof.
  • Orthologs include but are not limited to Streptococcus pyogenes Cas9 (“spCas9”), Cas 9 from Streptococcus
  • thermophiles Legionella pneumophilia, Neisseria lactamica, Neisseria meningitides, Francisella novicida; and Cpfl (which performs cutting functions analogous to Cas9) from various bacterial species including Acidaminococcus spp. and Francisella novicida U112.
  • TALEN transcription activator-like effector nucleases
  • TALE transcription activator-like effector nucleases
  • TALEs are proteins secreted by Xanthomonas bacteria.
  • the DNA binding domain contains a repeated, highly conserved 33-34 amino acid sequence, with the exception of the l2th and 13th amino acids.
  • TALEN TALEN
  • N nuclease
  • Fokl a nuclease
  • Several mutations to Fokl have been made for its use in TALENs; these, for example, improve cleavage specificity or activity. Cermak et al. (2011) Nucl. Acids Res. 39: e82; Miller et al. (2011) Nature Biotech. 29: 143-8; Hockemeyer et al. (2011) Nature Biotech.
  • the Fokl domain functions as a dimer, requiring two constructs with unique DNA binding domains for sites in the target genome with proper orientation and spacing. Both the number of amino acid residues between the TALE DNA binding domain and the Fokl cleavage domain and the number of bases between the two individual TALEN binding sites appear to be important parameters for achieving high levels of activity. Miller et al. (2011) Nature Biotech. 29: 143-8.
  • TALENs specific to sequences in immune cells can be constructed using any method known in the art, including various schemes using modular components. Zhang et al. (2011) Nature Biotech. 29: 149-53; Geibler et al. (2011) PLoS ONE 6: el9509.
  • ZFN Zinc Finger Nuclease
  • a ZFN refers to engineered nucleases that comprise a non-specific DNA-cleaving nuclease fused to a zinc finger DNA binding domain, which can target DNA sequences and be used for genome editing.
  • a ZFN comprises a Fokl nuclease domain (or derivative thereof) fused to a DNA-binding domain.
  • the DNA-binding domain comprises one or more zinc fingers.
  • a zinc finger is a small protein structural motif stabilized by one or more zinc ions.
  • a zinc finger can comprise, for example, Cys2His2, and can recognize an approximately 3-bp sequence.
  • Various zinc fingers of known specificity can be combined to produce multi-finger polypeptides which recognize about 6, 9, 12, 15 or l8-bp sequences.
  • selection and modular assembly techniques are available to generate zinc fingers (and combinations thereof) recognizing specific sequences, including phage display, yeast one-hybrid systems, bacterial one-hybrid and two-hybrid systems, and mammalian cells.
  • a ZFN must dimerize to cleave DNA. Thus, a pair of ZFNs are required to target non-palindromic DNA sites.
  • ZFNs specific to sequences in immune cells can be constructed using any method known in the art. See, e.g., Provasi (2011) Nature Med. 18: 807-815; Torikai (2013) Blood 122: 1341-1349; Cathomen et al. (2008) Mol. Ther. 16: 1200-7; Guo et al. (2010) J. Mol. Bioi. 400: 96; U.S. Patent Publication 201110158957; and U.S. Patent Publication 2012/0060230.
  • the agent may decrease the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • the agent may be an OLFR antagonist.
  • the OLFR antagonist may be citral, a solvate or prodrug thereof.
  • the OLFR antagonist may be methylcinnamaldehyde, hydrocinnamaldehyde, bourgeonal, undecanal, methyl isoeugenol a solvate or prodrug thereof.
  • the antagonist may be selected from the list of antagonists provided in Table 9 or a solvate or prodrug thereof.
  • the agent may decrease the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the methods, uses, and kits disclosed herein may comprise one or more agents that decrease or inhibit the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • the agent may be a gene silencing agent that inhibits the expression of a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • the agent may be an antibody, fragment, derivative, or mimetic thereof.
  • the antibody, fragment, derivative, or mimetic thereof may bind to an OLFR.
  • the agent may be an antibody that binds to an OLFR listed in any one of Tables 1-9 and FIGs. 2A-2B.
  • the agent may be an antibody that binds to an OLFR listed in Table 7.
  • the agent may be an antibody that binds to an OLFR selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the antibody, fragment, derivative, or mimetic thereof may bind to a ligand of an OLFR.
  • the antibody, fragment, derivative, or mimetic thereof may bind to a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • RTP2 receptor transporting protein 2
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the antibody may be polyclonal, monoclonal, multispecific (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.
  • Antibodies can be isolated from any suitable biological source, e.g., murine, rat, sheep and canine.
  • the antibody may be a human antibody, humanized antibody, or chimeric antibody.
  • the antibody may be a human monoclonal antibody.
  • the antibody may be a recombinant human antibody.
  • the terms“antibody,”“antibodies” and“immunoglobulin” includes whole antibodies and any antigen binding fragment or a single chain thereof.
  • the term“antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule.
  • immunoglobulins also include immunoglobulins of any isotype, fragments of antibodies which retain specific binding to antigen, including, but not limited to, Fab, Fab', F(ab) 2 , Fv, scFv, dsFv, Fd fragments, dAb, VH, VL, VhH, and V-NAR domains; minibodies, diabodies, triabodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from antibody fragments and one or more isolated.
  • CDR complementarity determining region
  • FR framework
  • immunoglobulin molecule contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues.
  • “anti-IHF” refers to an antibody that binds to the IHF protein.
  • the specific antibody may have affinity or bind to proteins other than the protein it was raised against.
  • anti-IHF while specifically raised against the IHF protein, may also bind other proteins that are related either through sequence homology or through structure homology.
  • “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single determinant on the antigen.
  • the antibodies may be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like.
  • the antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like.
  • the antibodies may also be bound to a solid support, including, but not limited to, polystyrene plates or beads, and the like.
  • Monoclonal antibodies may be generated using hybridoma techniques or recombinant DNA methods known in the art.
  • a hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody producing cancer cell, usually a myeloma or lymphoma.
  • a hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody.
  • Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest, and screening of antibody display libraries in cells, phage, or similar systems.
  • human antibody as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • the human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • the term“human antibody” as used herein is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • the term“human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, C L , C H domains (e.g., Cm, Cm, Cm), hinge, (VL, VH)) is substantially non- immunogenic in humans, with only minor sequence changes or variations.
  • antibodies designated primate monkey, baboon, chimpanzee, etc.
  • rodent mouse, rat, rabbit, guinea pig, hamster, and the like
  • other mammals designate such species, sub genus, genus, sub-family, family specific antibodies.
  • chimeric antibodies include any combination of the above.
  • a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes. Further, when a human antibody is a single chain antibody, it can comprise a linker peptide that is not found in native human antibodies.
  • an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain.
  • linker peptides are considered to be of human origin.
  • a human antibody is“derived from” a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, e.g., by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library.
  • a human antibody that is“derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins.
  • a selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences).
  • a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene.
  • a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene.
  • the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene.
  • A“human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. The term also intends recombinant human antibodies. Methods to making these antibodies are described herein.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • Such recombinant human antibodies have variable and constant regions derived from human germline
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. Methods to making these antibodies are described herein.
  • chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species.
  • immunoglobulin refers to a human/non-human chimeric antibody that contains a minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity.
  • donor antibody such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity.
  • Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody.
  • the humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody.
  • Fc immunoglobulin constant region
  • humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody.
  • the humanized antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions.
  • Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, serine-threonine and asparagine-glutamine.
  • polyclonal antibody or“polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope.
  • the term“antibody derivative” comprises a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids are chemically modified by alkylation, pegylation, acylation, ester formation or amide formation or the like, e.g., for linking the antibody to a second molecule.
  • the methods, uses, and kits disclosed herein may comprise one or more agents that decrease or inhibit expression or secretion of an inflammatory cytokine.
  • the inflammatory cytokine may be selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • kits comprising any of the agents disclosed herein.
  • the kit comprises an agent that modulates the activity of an OLFR and instructions for use.
  • the kit comprises an agent that increases the activity of an OLFR and instructions for use.
  • the kit may comprise an agent that increases the expression of an OLFR and instructions for use.
  • the kit may comprise an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell and instructions for use.
  • the kit may comprise an agent that decreases the activity of an OLFR and instructions for use.
  • the kit may comprise an agent that decreases the expression of an OLFR and instructions for use.
  • the kit may comprise an agent that decreases or inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell and instructions for use.
  • the kit may comprise a ligand of an olfactory receptor (OLFR) and instructions for use.
  • the kit may comprise an olfactory receptor (OLFR) agonist and instructions for use.
  • the kit may comprise an olfactory receptor (OLFR) antagonist and instructions for use.
  • the kit may comprise octanal and instructions for use.
  • the kit may comprise citral and instructions for use.
  • the kit may comprise a gene silencing agent that targets an olfactory receptor (OLFR) and instructions for use.
  • the kit may comprise a gene silencing agent that targets a ligand of an olfactory receptor (OLFR) and instructions for use.
  • the kit may comprise a gene silencing agent that targets one or more proteins selected from the group consisting of a receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal) and instructions for use.
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • kits disclosed herein may further comprise one or more pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein.
  • Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They may be selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the methods, uses, and kits disclosed herein may comprise administering an agent or instructions to administer an agent to a subject in need thereof.
  • administering can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and method of determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non- limiting examples of route of administration include oral administration, nasal administration, injection, and topical application.
  • An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient, and the disease being treated.
  • an effective amount refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical
  • the effective amount is the amount sufficient to result in a protective response against a pathogen. In other embodiments, the effective amount of an immunogenic composition is the amount sufficient to result in antibody generation against the antigen. In some embodiments, the effective amount is the amount required to confer passive immunity on a subject in need thereof. With respect to immunogenic compositions, in some embodiments the effective amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health/responsiveness of the subject's immune system, in addition to the factors described above. The skilled artisan will be able to determine appropriate amounts depending on these and other factors.
  • the terms“treat” or“treatment” may refer to any prevention or delay in onset, reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort or function, decrease in severity of the condition or disease state, decrease in the occurrence of a given condition or disease or condition or disease symptoms in a patient etc.
  • the effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient prior to, or after cessation of, treatment.
  • the treatment may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
  • a method of treatment results in partial or complete destruction of the neoplastic, tumor, cancer or malignant cell mass; a reduction in volume, size or numbers of cells of the neoplastic, tumor, cancer or malignant cell mass;
  • a method of treatment results in reducing or decreasing severity, duration or frequency of an adverse symptom or complication associated with or caused by the neoplasia, tumor, cancer or malignancy.
  • a method of treatment results in reducing or decreasing pain, discomfort, nausea, weakness or lethargy.
  • a method of treatment results in increased energy, appetite, improved mobility or psychological well being.
  • a method of treatment comprises administering a therapeutically effective amount of an agent to a subject, wherein the agent modulates expression or activity of one or more olfactory receptor listed in any of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, FIG. 2A, and FIG. 2B.
  • therapeutically effective amount as used herein is meant a dose that produces effects for which it is administered (e.g. treating or preventing a disease or disorder).
  • the exact dose and formulation will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g. , Lieberman, Pharmaceutical Dosage Forms (vols.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as“-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5 -fold, or more effect over a standard control.
  • a therapeutically effective dose or amount may ameliorate one or more symptoms of a disease.
  • a therapeutically effective dose or amount may prevent or delay the onset of a disease or one or more symptoms of a disease when the effect for which it is being administered is to treat a person who is at risk of developing the disease.
  • the present inventions further provide novel agents identified by the assays described herein and use of such agent in the methods of treatment described herein.
  • first, second, third, fourth, fifth, etc. predictor gene or a “positive or negative predictor gene” includes a plurality of such first, second, third, fourth, fifth, etc., genes, or a plurality of positive and/or negative predictor genes.
  • Reference to a number with more (greater) or less than includes any number greater or less than the reference number, respectively.
  • a reference to less than 30,000 includes 29,999, 29,998, 29,997, etc. all the way down to the number one (1); and less than 20,000, includes 19,999, 19,998, 19,997, etc. all the way down to the number one (1).
  • Reference to a range of 1-5 fold therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5, fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5, fold, etc., and so forth.
  • Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series.
  • 2-72 hours, 2-48 hours, 4-24 hours, 4-18 hours and 6-12 hours includes ranges of 2-6 hours, 2-18 hours, 2-24 hours, etc., and 4-27 hours, 4-48 hours, 4-6 hours, etc.
  • the invention is generally disclosed herein using affirmative language to describe the numerous embodiments and aspects.
  • the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, or procedures.
  • materials and/or method steps are excluded.
  • the invention is generally not expressed herein in terms of what the invention does not include aspects that are not expressly excluded in the invention are nevertheless disclosed herein.
  • Example 1 Effect of Citral on Expression of Inflammatory genes (CCL2. CCL4.
  • Gene expression analysis was performed by harvesting whole aortas from apoE /_ mice kept on western diet (WD) for 2 weeks and treating for l2h with DMSO (Ctrl), citral (Cit, IOOmM), octanal (Oct, 10mM in DMSO) or lipopolysaccharide (lps, 0.5pg/mL in DMSO) alone or in combination. After the incubation, aortas were transferred in Trizol reagent (lml) and digested with gentleMACSTM Dissociator (Millteny).
  • FIG. 1A shows the results of a gene expression analysis of CCL2, CCL4, TNF and iNOS after treatment with the Olfr2 inhibitor citral alone or in combination with octanal and LPS. As shown in FIG. 3 A, citral completely blocked the increase in CCL2, CCL4, TNF and iNOS, both in the presence and absence of LPS.
  • FIG. 1C shows pictures of pinned aortas of mice treated with citral or saline (untreated).
  • the citral-treated Apoe- /- mice showed significantly reduced atherosclerotic lesions, from ⁇ 8% of the aortic area to ⁇ 5% (P ⁇ .02).
  • blocking Olfr2 is anti-atherosclerotic, showing that Olfr2 contributes to atherosclerosis.
  • Atherosclerosis is an inflammatory disease of the arterial wall driven by macrophages and other immune cells.
  • Olfactory receptors (Olfrs) are G-protein coupled receptors expressed in olfactory epithelial cells and are responsible for the sense of smell.
  • Rtp2 and the cyclic nucleotide-gated ion channel subunits Cngal -4 and Cngbl were unexpectedly found to be expressed (Table 2). Some of these genes were detectable even in aortic macrophages from mice without atherosclerosis, and many were upregulated in response to LPS (FIG. 2A, Table 1).
  • Several microarray datasets (Affymetrix mouse gene 1.0 ST array type) were used for the comparison: GSE68968 Vascular Mf; GSE77104 BMDMs, GSE43075 peritoneal (PT)
  • FIG. 2B displays a heat map of expressed Olfrs with known human orthologues.
  • 582 have known human orthologues (Olfrs sharing the same human orthologue are included), 280 of which (48%) were expressed in vascular macrophages from LPS treated mice (FIG. 2B).
  • vascular macrophages express hundreds of olfactory receptors including Olfr2, a receptor for octanal. They also express Rtpl, Rtp2, Reep3, Acy3 and Gnal, accessory molecules needed for Olfr signaling and trafficking. Ligation of the human orthologue of Olfr2 (OR6A2), expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, is strongly pro-inflammatory. In this example, the role of Olfr2 in atherosclerosis is investigated.
  • Olfr2 (human orthologue: OR6A2) is investigated in this example because (1) its expression is increased in LPS treated vascular macrophages, (2) is expressed in bone marrow-derived macrophages (BMDMs), (3) has known ligands (aliphatic aldehydes including octanal), (4) has a known inhibitor (citral), (5) has a human orthologue (OR2A6), which (6) is expressed in human carotid endarteriectomy samples and human monocyte- derived macrophages.
  • BMDMs bone marrow-derived macrophages
  • OR2A6 human orthologue
  • Olfr2 binds medium-chain aliphatic aldehydes such as octanal with an EC50 of ⁇ 10 mM 15 ’ 16 .
  • Octanal is a 8-carbon aldehyde also known as fatty aldehyde that is produced by reduction of the carboxy group of caprylic acid (octanoic acid) or via lipid peroxidation during oxidative stress 17 .
  • Olfr2 expression in BMDMs was investigated. Briefly, bone marrow cells from Apoe A mice were stimulated with MCSF (20 ng/ml) for 7 d to generate BMDMs, which were left untreated or incubated with the Olfr2 agonist octanal (Oct, 10 mM), LPS, (500 ng/mL), or with both for 12 h.
  • Olfr2 agonist octanal Oct, 10 mM
  • LPS 500 ng/mL
  • FIGs. 3C-D demonstrated surface expression of Olfr2.
  • Cell surface and intracellular Olfr2 expression was confirmed by immunofluorescence (FIG. 3E).
  • Olfr2 expression in aortas harvested from western-type diet (WD)-fed male mice (n 5) was investigated 18 . Briefly, whole aortas were harvested from Apoe ⁇ mice fed western-like diet (WD) for 2 weeks and treated as described above. Relative expression of Olfr2 quantified by real time PCR analysis of Olfr2 expression normalized to expression of Gapdh and untreated control.
  • aortic Olfr2 mRNA, Rtpl and Rtp2 mRNA were found to be induced by LPS treatment ex vivo and significantly enhanced by adding octanal. Olfr2 expression was confirmed at the protein level on F4/80 + vascular endotanal.
  • Olfr2 expression in T cells and B cells was also investigated. Briefly, whole aortas were harvested from Apoe-/- mice kept on western diet (WD) for at least 2 weeks incubated with Octanal (Oct,l0pM) and lipopolysaccharide (LPS, 500ng/mL) for l2h. Cells were harvested and stained for Olfr2 detection (as described in FIG. 3E) and analyzed by flow cytometry (LSRII, BD Biosciences).
  • other aortic immune cell populations such as CD4 + T cells and CDl9 + B cells, did not show significant Olfr2 expression (FIGs. 5A-B).
  • FIG. 6B shows Olfr2 function in monocytes reported as TNF MFI multiplied to the cell events n 5 per group. Data are presented as means ⁇ SEM. * p ⁇ 0.05, ** p ⁇ 0.01, *** p ⁇ 0.005, **** p ⁇ 0.001. p calculated by One-Way ANOVA test, Tukey's multiple comparisons test.
  • Olfr2 ligation on inflammatory responses was investigated by measuring intracellular free calcium (Ca2 + ) in vascular macrophages. Briefly, mouse aortic cell suspensions were loaded with 2 mM Fluo-4 at 37 °C for 30 min, then washed and incubated with cell surface markers at RT for 20 min. CD45 + , live, dump channel (TCRb , CD19 ), F4/80 + macrophages were analyzed by flow cytometry. Olfr2 agonist Oct (10pM), and antagonist Cit (IOOmM) alone or combined (Oct+Cit) were added 60 seconds (s) after the acquisition started. DMSO (0.1%) was injected as a control (Ctrl).
  • FIG. 7A To test the functionality of Olfr2, time-resolved calcium flux in mouse vascular macrophages by flow cytometry was studied (FIG. 7A). Octanal induced a highly significant increase in intracellular free calcium at 100 and 125 s after injection, consistent with the known calcium dynamics of Olfrs 15 (FIG. 7B). This calcium flux was completely blocked by the Olfr2 inhibitor citral 9,16 (FIG. 7B). No calcium signal was detected in other immune cells (FIGs. 8A-B).
  • FIG. 8A-B To test the functionality of Olfr2, time-resolved calcium flux in mouse vascular macrophages by flow cytometry was studied (FIG. 7A).
  • FIG. 8A shows dump channel ⁇ !- cells (TCRb+, and CD19+), loaded with 2mM Fluo-4 before and after addition of Olfr2 agonist octanal (Oct IOmM), and antagonist Citral (Cit IOOmM) alone or combined (Oct+Cit).
  • Oct, and Cit injected at 60 seconds.
  • Whole aortas were digested, stained with Fluo4 (2mM) at 37°C for 30 min, then washed and incubated with cell surface markers at RT for 20 min.
  • CD45+, live, dump channel-!- (TCRb+, and CD19+) cells were analyzed by flow cytometry.
  • FIG. 8B shows the time average Median Fluorescence Intensity (MFI) of Fluo-4 is reported. SD is calculated among the cells for each time point (n 20-50). The analysis is made out one of three experiments.
  • MFI Median Fluorescence Intensity
  • An early step in atherosclerosis is the subendothelial retention of lipoproteins, which then triggers a non-resolving inflammatory process that over time drives plaque progression 20,21 .
  • Macrophages contribute to the inflammatory response and plaque formation by producing pro-inflammatory cytokines, such as interleukin- 1b (IL- 1 b) and tumor necrosis factor (TNF), chemokines including CCL2 and CCL4, and inducible nitric oxide synthase (iNOS) 22 .
  • IL- 1 b interleukin- 1b
  • TNF tumor necrosis factor
  • chemokines including CCL2 and CCL4
  • iNOS inducible nitric oxide synthase
  • Most vascular macrophages derive from CX3CRl + embryonic precursors with a postnatal contribution from bone marrow-derived monocytes that colonize the tissue immediately after birth 23,24 .
  • vascular macrophages proliferate locally 25 .
  • plaques contain several phenotypically distinct macrophage subsets 26 28 .
  • four major macrophage populations were found in atherosclerotic aortas: a resident-like, an inflammatory and a TREM2 + subset 26 and foam cells 28 .
  • Macrophages are known producers of one of the most prominent cytokines driving atherosclerosis, IIMb 29 .
  • IL- 1 b production and secretion requires assembly of the inflammasome, a cytoplasmic complex containing several proteins that serves as a molecular platform for activation of the cysteine protease caspase 30,31 .
  • BMDMs were primed with low-dose LPS (50 ng/mL) for 18 h followed by exposure to octanal alone or together with citral.
  • IL- 1 b protein in the supernatant was quantified by a cytokine bead array.
  • FIG. 10A Stable isotope dilution HPLC with on-line tandem mass spectrometry (LC/MS/MS) (FIG. 10A) showed detectable levels of octanal in all mice.
  • octanal ranged between 1.5 and 2.5 mM (FIG. 10B).
  • the octanal level was significantly increased to an average of 3.5 pM in mice fed WD (FIG. 10B).
  • Octanal was also elevated in Apoe 2 mice receiving CD and WD (FIG. 10C).
  • mice were fed a high-fat diet for 12 weeks. Circulating metabolic parameters (total cholesterol, high-density lipoprotein-cholesterol, and triglycerides), blood leukocyte counts and animal weights were similar between the 3 groups (FIG. 12). Aortic arch lesions in Rtpl/Rtp2 / chimeric mice were significantly reduced compared to Rtpl/Rtp2 +/+ recipient mice (FIG. 10J). Taken together, Olfr2 and possibly other Olfrs regulated by Rtpl and 2 promote atherosclerosis in mice. Inhibition of Olfr2 limits atherosclerosis in mice.
  • OR6A2 mRNA expression was detectable, increased by LPS and further augmented by adding octanal (FIG. 13Bi).
  • OR6A2 protein surface expression in hMDMs was confirmed by flow cytometry (FIG. 13Bii and iii). Immunostaining suggests that OR6A2 expression in LPS+octanal-treated hMDMs may be polarized (FIG. 13C).
  • OR6A2 was silenced in hMDMs by small interference RNAs (SiOR6A2). LPS- and ocatanal-treated hMDMs exhibited reduced expression of IL6, NOS2 and TNF compared to hMDMs treated with scrambled siRNAs (SiCtrl) (FIG. 13G).
  • Olfrs The discovery of a new class of GPCRs, Olfrs, that enhance atherosclerosis suggest a new class of drug targets.
  • the octanal receptor Olfr2 and its human orthologue OR6A2 are expressed on aortic vascular macrophages, mouse BMDMs, human hMDMs and human atherosclerotic lesions.
  • Olfr2/OR6A2 expression is increased by LPS and further elevated in the presence of octanal at the mRNA and protein level.
  • Olfr2 ligation by octanal induces inflammatory cytokines and chemokines in mouse and human macrophages.
  • mice with the known Olfr2 agonist octanal exacerbated atherosclerosis, while blocking Olfr2 by citral or impairing Olfr trafficking by Rtpl/Rtp2 _/ protected mice from atherosclerosis. Since blocking Olfr2 or impairing the trafficking of Olfrs suggests that octanal and perhaps other natural endogenous volatile compounds significantly drive atherosclerosis in vivo. Relevance to human atherosclerosis is suggested by the decreased inflammatory activation of octanai-stimulated hMDMs depleted of OR6A2, the observation of octanal in human blood serum and the presence of OR6A2 in all 126 human
  • Apoe ⁇ , Ldlr /_ and wt mice on C57BL/6J background were purchased from Jackson Laboratories. Rtpl/Rtp2 ⁇ /+ breeding pairs were kindly provided by Dr. Hiroaki Matsunami from the Duke University Medical Center. Gender-matched mice (8-10 weeks old) were used in all experiments unless specified. Mice were housed in a conventional environment and had access to chow diet ad libitum. From 8-10 weeks of age on, Apoe _/ and C57BL/6J mice were fed a western-like diet (WD) with 42% from fat (Harlan Labs Cat #: TD.88137) and remained on WD until sacrifice. Ldl ' male mice (8-10 weeks of age) were used for bone marrow transplantation experiments as specify in detail below.
  • aorta was surgically removed and carefully cleaned of adipose tissue in situ. Aortas were either kept whole or enzymatically digested as previously described 18 . In brief, aortas were cut into small pieces and individually digested lh at 37 °C in HBSS containing 450U/mL Collagenase I (Sigma Aldrich), 250 U/mL Collagenase XI (Sigma Aldrich), 120 U/mL Hyaluronidase (Sigma Aldrich), and l20U/mL DNase I (Worthington).
  • the digested aortic cell suspension was filtered through a 50pm cell strainer (Partec) and washed with warm 37°C RPMI-1640 medium (Gibco-ThermoFischer) supplemented with 10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin solution (Gibco- ThermoFischer) (from here on referred to as culture medium).
  • Mouse blood was collected in ethylenediamine tetraacetic acid (EDTA)-coated tubes (Sarstedt) by cardiac heart puncture during organ harvest.
  • EDTA ethylenediamine tetraacetic acid
  • Circulating leukocytes were obtained from full mouse blood incubated with 10 mL of IX Red Blood Cell (RBC) Lysis Buffer (eBioscience) for 10 min at room
  • RT temperature in the dark. Subsequently, cells were washed twice with culture medium and used for further flow cytometry studies.
  • Mouse bone marrow was isolated from femurs and tibiae flushed with 5 ml ice cold RPMI-1640 medium. Bone marrow cells were passed through a 70 pm cell strainer (BioPioneer) and resuspended at lxlO 6 cells/ml in culture medium supplemented with 20 ng/mL of mouse recombinant macrophage-colony stimulating factor (M-CSF; Peprotech). Cells were cultured at 37 °C and 5% CO2U1 a 3.8 cm 2 (Thermo Fischer Scientific) dish. After 3 days, 5 ml of fresh medium were added to the culture. On day 7, floating cells were discarded and adherent cells used for further studies.
  • M-CSF mouse recombinant macrophage-colony stimulating factor
  • hMDMs Human monocyte derived macrophages
  • PBMCs Peripheral blood mononuclear cells
  • NBDP La Jolla Institute for Immunology’s in-house Normal Blood Donor Program
  • Human monocytes were enriched from PBMCs by the EasySepTM Human Monocyte Isolation Kit (StemCell) according to the
  • mice were fed WD for 2 weeks before sacrifice for aorta explant culture.
  • Whole aortas were incubated in culture medium with DMSO (0.1% as a vehicle), octanal (Oct, IOmM), LPS (500 ng/mL) alone or octanal and LPS combined (LPS+Oct) for 12 h at 37 °C and 5% CO2.
  • DMSO octanal
  • IOmM octanal
  • LPS 500 ng/mL
  • LPS+Oct LPS combined
  • mice Male Apoe A mice (9 to 10 wks old) were fed WD for 4 weeks. Oct or Cit were diluted in sterile phosphate buffered saline (PBS) (Gibco) at a final concentration of 10pg/g. IOOmI were injected intraperitoneally (i.p.) every 3 days for 4 weeks (12 injections total) while maintaining WD administration. PBS + 0.1% DMSO (Sigma Aldrich) was injected as a vehicle control following the same protocol. Mice were sacrificed, perfused with PBS implemented with 2% heparin (Fresenius Kabi USA, LLC) and aortas removed for en face atherosclerotic lesion assessment. Mouse whole blood (heart puncture) was collected in EDTA tubes. Leukocyte blood counts were determined with HemaVet 950 (Drew
  • mice Ten-week-old Ldlr 7 male mice were irradiated twice 2-4h apart with 550 rads X-ray irradiation to induce systemic medullar aplasia. Irradiated mice were repopulated intravenously (tail vein) with bone marrow cells (5xl0 6 cells) isolated from femurs and tibias of 10-week-old Rtpl/Rtp2 +/+ , Rtpl/Rtp2 +/ , Rtp I /Rtp2 mice, respectively. After a 2- week recovery period, mice were fed a high cholesterol diet (product number D12108C, Research Diets Inc.) for additional 12 wks.
  • a high cholesterol diet product number D12108C, Research Diets Inc.
  • mice were sacrificed, perfused with PBS implemented with 2% heparin (Fresenius Kabi USA, LLC) and aortas removed for en face atherosclerotic lesion assessment.
  • Blood was collected in EDTA tubes by cardiac heart puncture.
  • Leukocyte blood counts were determined with HemaVet 950 (Drew Scientific). Plasma was collected from blood centrifuged at 3000g for 15 min at 4 °C and stored -80 °C until further analysis.
  • Femurs and tibias were also collected for BMDMs differentiation flowing the same protocol already described, and furtherly used for flow cytometry and western blot analysis of 01fr2 expression.
  • each aorta was pinned out after 4% paraformaldehyde incubation at room temperature for at least 2 hours. Staining for atherosclerotic plaque was performed by incubating samples in Sudan IV. Microphotographs of the luminal (endothelial) aspect were of the aortic surface were analyzed using Photoshop CS (Adobe Systems).
  • Atherosclerotic lesion size measurement was performed by blinded investigators using Image-Pro Premier software (Media Cybernetics).
  • BMDMs and hMDMs were incubated in culture media for 12 h at 37 °C and 5% CO2 with Oct, (10pM), LPS (500ng/mL) alone or combined with Oct (LPS+ Oct) and DMSO (0.1%) as a control and lysed with Qiazol (500pL; Qiagen).
  • Oct, (10pM) LPS (500ng/mL) alone or combined with Oct (LPS+ Oct) and DMSO (0.1%) as a control and lysed with Qiazol (500pL; Qiagen).
  • whole aortas incubated as previously described were transferred into Qiazol (500pl; Qiagen) and digested with gentleMACSTM Dissociator (Miltenyi).
  • RNA extraction was performed using a Qiazol/RNAeasy micro kit hybrid protocol (Qiagen).
  • RNA purification After electroporation, cells were transferred to RPMI-1640 medium supplemented with 20% of fetal calf serum, 100 U/mL penicillin and 100 pg/mL streptomycin, and 50 ng/mL rhMCSF (Peprotech) and cultured in 48-well plates at 37 °C and 5% CO2 for 48 h. Cell viability was determined by a trypan blue exclusion assay. Cells were further treated in culture medium for 12 h at 37 °C and 5% CO2 with Oct, (10mM), LPS (500ng/mL) alone or combined with Oct (LPS+ Oct), and DMSO (0.1%) as a control and subsequently lysed in Qiazol (500 pl) for RNA purification. OR6A2, TNF, 1L6, and NOS2 expression levels were analyzed by Real Time PCR as described before.
  • BMDMs, hMDMs, mouse blood leukocytes and whole mount aortas were incubated in culture medium with Oct, (10mM), LPS, (500 ng/mL) alone or combined (LPS+Oct) for l2h at 37 °C and 5% CO2. After the incubation aortas were cut into small pieces and digested for cell suspension as previously described 18 .
  • aortic cell suspensions, BMDMs, blood leukocytes and hMDMs were incubated for 1 h with mouse or human Fc block solution, respectively, and stained with primary antibodies detecting Olfr2 (1:500, Thermo Fischer Scientific) or OR6A2 (1 :500, Sigma Aldrich) for 1 h at RT. Normal rabbit IgG (1 :500 Sigma Aldrich) incubated cells were used as a control.
  • Aortic cells were stained in the dark for 20 min at RT with a mixture of CD45-PerCP, CDllb- PECy7, CDl lc-BV605, TCR -BV7ll, CD4-PE-AlexaFluor6lO, CDl9-APCCy7, GR1- BV786, F4/80-BV421 (Biolegend) antibodies and LD Yellow fixable dye.
  • Mouse blood leukocytes were stained in the dark for 20 min at RT with a mixture of CD45-PerCP, CDl l5-PECy7, Ly6C-BV42l, TCRP-BV7ll, CD4-PE-AlexaFluor6lO, CDl9-APCCy7, (Bio legend) antibodies and LD Yellow fixable dye.
  • hMDMs were stained in the dark for 20 min at RT with LD Yellow fixable dye and anti-human CD45-AF700.
  • Aortic cell suspensions were obtained as mentioned above, stained with CD45-PerCP, CDl lb-PECy7, CDl lc-BV605, TCRP-BV7ll, CD4-PE-AlexaFluor6lO, CDl9-APCCy7, GR1-BV786, F4/80-BV421 and LD Yellow fixable dye (Invitrogen).
  • Blood leukocytes were stained with CD45-PerCP, CDll5-PECy7, Ly6C-BV42l, TCRP-/CD4/CDl9- APCCy7 (dump channel), and LD Yellow fixable dye.
  • Aortic cell suspensions obtained as previously described 18 were pre-incubated with extracellular markers for vascular macrophages including CD45-PerCP, TCR /CD4- APCCy7 (Dump Channel), F4/80-BV421 and LD Yellow fixable dye (Invitrogen) for 20 min in Fc block solution at RT in the dark.
  • Aortic cell suspensions were than washed twice and loaded with 2 mM of Fluo4 dye (Thermo Fischer Scientific) for 30 min at 37 °C.
  • Nitrocellulose membranes (Amersham Protran 0.2pm NC) using the Mini Trans-blot electrophoretic transfer cell (Bio-Rad). Membranes were blocked in 5% bovine serum albumin (Sigma) prepared in tris-buffered saline with 0.1% Tween-20 (TBST). Membranes were incubated overnight at 4 °C with 1:1000 diluted Olfr2 (Thermo Fischer Scientific) or tubulin (CST) primary antibodies. Membranes were washed thrice with TBST and incubated with a HRP-conjugated secondary antibody (Promega) for 1 h at RT. Blots were again washed thrice with TBST and developed using a chemiluminescent substrate (Thermo Fischer Scientific). Protein bands were visualized with the ChemiDoc MP Imaging System (Bio-Rad) using Image Lab software.
  • Affymetrix gene chip data were normalized using the robust multi-array average (RMA) method (log2, background-corrected, quantile normalized). Correlation analyses were based on Pearson’s correlation. Gene expression among dataset were normalized based on Gapdh expression (Xmax) using the ranking strategy: X-Xmin/Xmax-Xmin. Heatmap analysis and visualization was performed applying Morpheus, so tlware.broadinsti tute.org/morpheus.
  • RNA-seq living CD45 + , TCR , CD19 , F4/80 + macrophages from aortas of Apoe _/ mice fed a WD for 20 weeks were FACS-sorted with the FACSArialll (BD Biosciences).
  • Sequencing libraries were prepared from purified RNA using the RNeasy Mini Kit (Qiagen).
  • Double stranded (ds)-cDNA was prepared using the SMART-seq v4 Ultra Low RNA Kit for Illumina Sequencing (Takara-Clontech) according to the manufacturer’s instructions.
  • cDNA was amplified using 11 cycles and eluted in 12 pL.
  • 5 pL of resulting cDNA was processed using a NexteraXT kit (Illumina, CA, USA) following manufacturer’ s instructions. Samples were pooled into two batches, loaded on an Illumina HiSeq4000 and sequenced with 50 base pair single end reads (SR50). Transcriptomes were mapped to the mmlO mouse genome. Post-mapping quality control checks were used to exclude poor quality samples.
  • BMDMs and hMDMs were cultured on p-Slide 8 well glass bottom (Ibidi) and treated as described above. Subsequent to incubation, cells were fixed with 2%
  • BMDMs and hMDMs were than stained with Olfr2 and OR6A2 primary antibodies [1 :500, Thermo Fischer Scientific (mouse Olfr2) and 1 :500 Sigma- Aldrich Co (human OR6A2)], respectively, for 1 h in Fc blocking solution.
  • Cells were then washed 5 times for 5 minutes with cold PBS and stained with secondary anti-rabbit IgG-AF488 (1:400, Thermo Fischer Scientific) for 30 min at 4 °C. Nuclear counterstaining with Hoechst (1:2500, Sigma) was performed for 10 min. Cells were then washed 5 times and imaged with a Zeiss LSM880 confocal scanning microscope. Image acquisition settings were adjusted with control samples (unstained sample, and isotypes control) and kept throughout the experiment.
  • aortae form Apoe _/ mice fed WD for 2 weeks were carefully cleaned in situ and fixed in 4% paraformaldehyde at 4 °C for 24 h. Subsequently, aortae were washed with PBS and transferred to 5 mL incubation buffer (2% FCS, 0.5% saponin, 0.1 % sodium azide) containing Olfr2 primary antibody (1:1000, Thermo Fischer Scientific) for and agitated for 24 h at 37 °C.
  • Aortas were then washed 5 times with PBS and stained while agitation in 5 mL incubation buffer containing secondary anti-rabbit IgG- AF555 (1 :500, Thermo Fischer Scientific), anti-mouse CD68-AF647 (1:200, Biolegend) and Hoechst (1:10000, Sigma) for 24 h at 37 °C.
  • Stained aortas were washed with PBS, opened longitudinally, mounted between glass slides, and imaged form the adventitial side with a Zeiss LSM880 confocal scanning microscope. Image acquisition settings were set with control samples (Unstained samples, CD68-AF647 FMO, and secondary anti-rabbit IgG-AF555 FMO) and maintained throughout the experiment. Image and scan processing were performed with Zen microscope software (Zeiss) and Imaris analysis software (Bitplane).
  • Mouse blood plasma was collected reto-orbitally from 8-10 weeks old Apoe A and WT mice fed WD or chow diet for 1 day.
  • Plasma octanal was derivatized with 3-nitrophenylhydrazine in the presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and detected by LC/MS/MS after injection onto a TitanTM C18 UHPLC Column (1.9 pm particle size, 10 cm x 2.1 mm, Supelco) with elution solvent generated by two pumps from solvent A, water + 0.01% formic acid and B, acetonitrile + 0.01% formic acid.
  • Example 4 Identification of OLFRs that modulate immune responses
  • AT Androstenone
  • IA Isovaleric Acid
  • NA N-Amil Acetate
  • PP Propyl propionate
  • OCT Octanal
  • these olfactory receptors may include those olfactory receptors listed in Table 7 or one or more of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, or OR6A2 or an ortholog, homologue, variant or derivative thereof.
  • the PEA technique also permits accurate assessment of protein levels with repeated measurements by requiring both dual recognition of correctly matched antibody pairs and DNA-barcoding from sequence-specific oligonucleotides to generate a signal (PLoS ONE. 20l4;9(4)).
  • the assay measures fold change in log 2 units.
  • the raw data are converted into a t-statistic which can be compared across assays. Data are presented as means ⁇ SEM. P value ⁇ 0.05 calculated by unpaired t-test.
  • This analysis confirmed that modulation of olfactory receptor expression or activity may increase or decrease the expression or activity of proteins involved with immune response, and as such increasing or decreasing expression or activity of olfactory receptors may be utilized to increase or decrease expression or activity of certain immune response-related proteins.
  • immune response-related proteins may include those genes listed in FIG. 16 and/or FIG. 17, or one or more of CCL5 (C-C Motif Chemokine Ligand 5), Tnfrsfl2a (Osteoprotegerin), Axin 1, Nadk, Ahr (Aryl hydrocarbon receptor), QDPR (quinoid dihydropteridine reductase), HGF (Hepatocyte Growth Factor), ADAM23, or Snap29.
  • CCL5 C-C Motif Chemokine Ligand 5
  • Tnfrsfl2a Steoprotegerin
  • Axin 1 Nadk
  • Ahr Aryl hydrocarbon receptor
  • QDPR quinoid dihydropteridine reductase
  • HGF Hepatocyte Growth Factor
  • ADAM23 AdAM23, or Snap29.
  • OLFR ligands There are different sources of OLFR ligands, including diet, bacterial microbiota metabolism of various precursors (including from diet), and naturally occurring octanal in the subject.
  • the role of gut microbiota in the production of ligands is demonstrated by generation of mice lacking gut microbiota which are found to have less concentrations of OLFR ligands than wild-type mice. For example, mice lacking gut microbiota are found to have 3 -fold less concentration of octanal than wild-type mice (FIG. 18).
  • an Olfr knockout mouse is prepared. These mice are treated with a ligand or agonist of the OLFR and show reduced atherosclerosis when compared to Apoe-/- mice and WT mice also treated with the ligand or agonist.
  • an Olfr2 knockout mouse is prepared and treated with octanal. These mice show reduced atherosclerosis when compared to Apoe-/- mice and WT mice also treated with octanal. As such, reduction of Olfr2 expression or activity reduces or inhibits inflammatory response.
  • olfactory receptor involvement in inflammasome activation/signaling is demonstrated.
  • Olfr2 binding to its ligand represents a Signal 2 or activation signal, promoting the maturation and secretion of pro-inflammatory cytokines interleukin l-beta (IL-1B) and interleukin 18 (IL-18).
  • IL-1B interleukin l-beta
  • IL-18 interleukin 18
  • olfactory receptor activation may result in the activation of nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors (NLRs) in the inflammasome.
  • NLRs leucine-rich repeat-containing receptors
  • NLRs including NALP3 (NACHT, LRR and PYD domains- containing protein 3, also known as cryopyrin) or NLRC4 (NLR family CARD domain- containing protein 4) are activated by OLFR2.
  • NALP3 NACHT, LRR and PYD domains- containing protein 3, also known as cryopyrin
  • NLRC4 NLR family CARD domain- containing protein 4
  • a novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175-187 (1991).
  • a method of modulating an immune response in a subject comprising modulating expression or activity of one or more olfactory receptors (OLFR).
  • OLFR olfactory receptors
  • modulation comprises one or more of inhibiting, decreasing, reducing, suppressing, limiting or controlling the immune response by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an autoimmune response, disorder or disease in a subject, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the undesirable or aberrant immune response, immune disorder, inflammatory response or inflammation, or an adverse symptom of the autoimmune response, disorder or disease in the subject.
  • inflammation or an adverse symptom of the autoimmune response, disorder or disease is swelling, pain, rash, headache, fever, nausea, diarrhea, bloat, lethargy, skeletal joint stiffness or tissue or cell damage.
  • the immune disorder, inflammatory response, inflammation, autoimmune response disorder or autoimmune disease comprises rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis, diabetes mellitus, multiple sclerosis,
  • encephalomyelitis myasthenia gravis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, atopic dermatitis, eczematous dermatitis, psoriasis,
  • IFNGR1, IFNGR2 interferon g receptor
  • IFNGR2 interferon g receptor
  • IFNGR2 interferon g receptor
  • interleukin 12 or interleukin 12 receptor deficiency immunodeficiency with thymoma
  • WAS protein deficiency Wiskott-Aldrich syndrome
  • ATM deficiency ataxia telangiectasia
  • SH2D1 A/SAP deficiency X-linked lymphoproliferative syndrome
  • hyper IgE syndrome hyper IgE syndrome.
  • any one of embodiments 1-5 wherein the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse cardiovascular event or cardiovascular disease by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • the adverse cardiovascular event or cardiovascular disease comprises coronary artery disease, peripheral artery disease, cerebrovascular disease, renal artery disease, stroke, myocardial infarction (heart attack), ischemic heart failure, transient ischemic attack or brain trauma, atherosclerosis, atherosclerotic plaque formation or elevated blood cholesterol.
  • the modulation comprises one or more of decreasing, reducing, inhibiting, suppressing, limiting or controlling atherosclerosis, by a method comprising administering to the subject an effective amount of an agent that inhibits the expression of or deactivates the OLFR.
  • any one of embodiments 1-5 wherein the method comprises one or more of reducing or inhibiting in a subject viral, bacterial or fungal infection, by a method comprising administering to the subject an effective amount of an agent that increases the expression of or activates the OLFR.
  • the modulation comprises one or more of comprising decreasing, reducing, inhibiting, suppressing, limiting or controlling an adverse symptom of the neoplasia, neoplastic disorder, tumor, cancer or malignancy, metastasis of a neoplasia, tumor, cancer or malignancy to other sites, or formation or establishment of a metastatic neoplasia, neoplastic disorder, tumor, cancer or malignancy to other sites distal from a primary neoplasia, neoplastic disorder, tumor, cancer or malignancy, or viral, bacterial or fungal infection by a method comprising administering to the subject an effective amount of an agent that increases the expression of or activates the OLFR.
  • neoplasia, neoplastic disorder, tumor, cancer or malignancy treated is a carcinoma, sarcoma, neuroblastoma, cervical cancer, hepatocellular cancer, mesothelioma, glioblastoma, myeloma, lymphoma, leukemia, adenoma, adenocarcinoma, glioma, glioblastoma, retinoblastoma, astrocytoma, oligodendrocytoma, meningioma, lymphosarcoma, liposarcoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma or melanoma; or a lung, thyroid, head or neck, nasopharynx, throat, nose or sinuses, brain, spine, breast, adrenal gland, pituitary gland
  • OLFR is selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • the agent is selected from the group of: a ligand or small molecule that binds to the OLFR or blocks the binding of the OLFR to the ligand or an agent that inhibits the expression of the OLFR by the cell.
  • the agent is selected from the group of an antibody, fragment or mimetic that binds to OLFR or an OLFR ligand, an anti- OLFR gene silencing agent, octanal, heptanal, or a prodrug or solvate thereof.
  • the agent modulates the OLFR by modulating the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is a protein selected from the group of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), or guanine nucleotide binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • RTP2 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide binding protein G(olf) subunit alpha
  • the agent is a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the inflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, interleukin 6 (IL-6), IL-1B, IL-18, and nitric oxide synthase 2 (NOS2).
  • TNF tumor necrosis factor
  • CCL2 C-C motif chemokine ligand 2
  • CCL4 CCL5
  • IL-6 interleukin 6
  • IL-1B interleukin 1B
  • IL-18 nitric oxide synthase 2
  • NOS2 nitric oxide synthase 2
  • a method of suppressing an immune response in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR), thereby suppressing an immune response in the subject.
  • OLFR olfactory receptor
  • OLFR is an OLFR listed in Table 7.
  • Table 7 The method of any of embodiments 29-31, wherein the OLFR is selected from the group consisting of OR7C1, OR7D4, OR10A6, OR11H6, OR4E2, OR10H1, and OR6A2.
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • RNAi molecule is selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • siRNA small interference RNA
  • shRNA short hairpin RNA
  • miRNA microRNA
  • OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • a method of increasing an immune response in a subject in need thereof comprising administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby increasing an immune response in the subject.
  • OLFR olfactory receptor
  • a method of suppressing an immune response in a subject in need thereof comprising administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell, thereby suppressing an immune response in the subject.
  • OLFR olfactory receptor
  • a method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of treating an autoimmune disease in a subject in need thereof comprising administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • a method of treating a cardiovascular disease in a subject in need thereof comprising administering to the subject an agent that decreases the expression of or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of a cardiovascular disease in a subject in need thereof comprising administering to the subject an agent that inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • a method of treating an infection in a subject in need thereof comprising administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of treating an infection in a subject in need thereof comprising administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • invention 49 or 50 wherein the infection is selected from the group consisting of a viral infection, bacterial infection, or fungal infection.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • a method of cancer in a subject in need thereof comprising administering to the subject an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • a method of modulating the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that modulates the expression or activity of an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of increasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that increases the expression of or activates an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of decreasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that decreases the expression of or inhibits an olfactory receptor (OLFR).
  • OLFR olfactory receptor
  • a method of modulating the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that modulates the trafficking of an olfactory receptor (OLFR) to a plasma membrane of the cell.
  • OLFR olfactory receptor
  • a method of increasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that increases or promotes the trafficking of an olfactory receptor (OLFR) to a plasma membrane of the cell.
  • OLFR olfactory receptor
  • a method of decreasing the expression or activity of one or more proteins involved in an immune response comprising contacting a cell with an agent that decreases or inhibits the trafficking of an olfactory receptor (OLFR) to a plasma membrane of a cell.
  • OLFR olfactory receptor
  • RNAi RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • RNAi molecule is selected from the group consisting of a small interference RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miRNA).
  • siRNA small interference RNA
  • shRNA short hairpin RNA
  • miRNA microRNA
  • OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • OLFR agonist is selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl-fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)-citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, acetophenone, amyl butyrate, nonanethiol, allyl phenyl acetate, N-amyl
  • any of embodiments 43, 49-55, 57, 59, and 60 wherein the agent is a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the agent comprises a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • the method of any one of embodiments 54-63, wherein the one or more proteins involved in an immune response is any of the proteins shown in FIGs. 16 and 17.
  • the method of any one of embodiments 54-63, wherein the one or more proteins involved in an immune response is a protein selected from CCL5 (C-C Motif Chemokine Ligand 5), Tnfrsfl2a (Osteoprotegerin), Axin 1, Nadk, Ahr (Aryl hydrocarbon receptor), QDPR (quinoid dihydropteridine reductase), HGF
  • a kit comprising an agent that modulates the activity of an OLFR and instructions for use.
  • RNA interference RNA interference
  • TALEN transcription activator-like effector nuclease
  • CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats
  • kit of any of embodiments 94-97 wherein the agent modulates the activity of the OLFR by inhibiting the binding of the OLFR with its ligand.
  • kits of embodiment 98, wherein the ligand is an OLFR ligand listed in Table 8.
  • kits of embodiment 100 wherein the OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • the OLFR antagonist is citral, undecanal, oxyphenylon, phenirat, methyl cinnamaldehyde, hydrocinamaldehyde, bourgeonal, ethylhexanoic acid, a-ionone, octanoic acid, a solvate or prodrug thereof.
  • the kit of embodiment 94 wherein the agent modulates the activity of the OLFR by inhibiting the trafficking of the OLFR to a plasma membrane of a cell.
  • the agent is an antibody, fragment or mimetic thereof that binds to an OLFR.
  • kits of embodiment 94, wherein the agent is an OLFR agonist wherein the agent is an OLFR agonist.
  • kits of embodiment 105 wherein the OLFR agonist is selected from the group consisting of octanal, coumarin, helional, lilial, b-ionone, androstenone, androstadienone, caramel furanone, 3 -phenyl propyl propionate, eugenol, ethil vanillin, 2-ethyl-fencol, isovaleric acid, nonanoic acid, butyl butyryllactate, butyric acid, isovaleric acid, propionic acid, N-amyl acetate, eugenol acetate, sandalwood, S-(-)-citronellol, S-(-)-citronellal, (+)-carvine, (-) carvone, (+) carvone, linalool, bourgeonal, acetophenone, amyl butyrate, nonanethiol, allyl phenyl acetate, N-amy
  • kits of embodiment 94 wherein the agent is a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • RTP2 receptor transporting protein 2
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • kits of embodiment 94 wherein the agent comprises a nucleotide encoding a protein selected from the group consisting of receptor transporting protein 1 (RTP1), RTP2, receptor expression enhancing protein 1 (REEP1), aminoacylase 3 (Acy3), and guanine nucleotide-binding protein G(olf) subunit alpha (Gnal).
  • RTP1 receptor transporting protein 1
  • REEP1 receptor expression enhancing protein 1
  • Acy3 aminoacylase 3
  • Gnal guanine nucleotide-binding protein G(olf) subunit alpha
  • Table 1 Olfactory receptors and accessory genes GAPDH ranked expression as displayed in the heatmap of Figure 1

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2021257905A3 (en) * 2020-06-17 2022-03-24 H. Lee Moffitt Cancer Center And Research Institute, Inc. Olfactory receptors for use as targets for antigen binding molecules to detect and treat cancer
WO2022128050A1 (en) * 2020-12-14 2022-06-23 Symrise Ag Medicament for fighting inflammation and pain
WO2023169996A1 (en) * 2022-03-07 2023-09-14 Fondazione Per L'istituto Oncologico Di Ricerca (Ior) Use of olfactory receptor or13a1 antagonists in the treatment of lymphomas
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US12290550B1 (en) 2023-12-27 2025-05-06 Olfactive Ai, Inc. Compositions and methods for treating endocrine diseases and disorders
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006008074A1 (de) * 2006-02-22 2007-08-23 RUHR-UNIVERSITäT BOCHUM Behandlung von Krebs mit Geruchsrezeptor-Liganden
US20110196383A1 (en) 2009-05-05 2011-08-11 Atherolysis Medical, Inc Atherosclerotic Plaque Dissolution Composition
US20120060230A1 (en) 2010-07-21 2012-03-08 Trevor Collingwood Methods and compositions for modification of a hla locus
WO2013061487A1 (ja) * 2011-10-26 2013-05-02 パナソニック株式会社 マウス嗅覚受容体Ｏｌｆｒ１５を細胞膜に発現する方法
CN103976987A (zh) 2014-06-04 2014-08-13 古天津 一种用于治疗动脉粥状硬化的组合物
WO2015028515A1 (en) * 2013-08-27 2015-03-05 Deutsches Krebsforschungszentrum Cytotoxic t cell response modifiers
CN106668050A (zh) 2017-01-22 2017-05-17 新乡医学院 治疗动脉粥样硬化的药物组合物及应用
US20180028443A1 (en) 2014-01-29 2018-02-01 Catherine Beaudin Use of biocompatible microdroplets for the treatment of atherosclerosis, heart disease and stroke

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101050436B1 (ko) * 2010-12-09 2011-07-19 연세대학교 산학협력단 대사질환과 연관된 후각수용체 유전자 및 그의 용도

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102006008074A1 (de) * 2006-02-22 2007-08-23 RUHR-UNIVERSITäT BOCHUM Behandlung von Krebs mit Geruchsrezeptor-Liganden
US20110196383A1 (en) 2009-05-05 2011-08-11 Atherolysis Medical, Inc Atherosclerotic Plaque Dissolution Composition
US20120060230A1 (en) 2010-07-21 2012-03-08 Trevor Collingwood Methods and compositions for modification of a hla locus
WO2013061487A1 (ja) * 2011-10-26 2013-05-02 パナソニック株式会社 マウス嗅覚受容体Ｏｌｆｒ１５を細胞膜に発現する方法
WO2015028515A1 (en) * 2013-08-27 2015-03-05 Deutsches Krebsforschungszentrum Cytotoxic t cell response modifiers
US20180028443A1 (en) 2014-01-29 2018-02-01 Catherine Beaudin Use of biocompatible microdroplets for the treatment of atherosclerosis, heart disease and stroke
CN103976987A (zh) 2014-06-04 2014-08-13 古天津 一种用于治疗动脉粥状硬化的组合物
CN106668050A (zh) 2017-01-22 2017-05-17 新乡医学院 治疗动脉粥样硬化的药物组合物及应用

Non-Patent Citations (72)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2003
AGRAWAL, N. ET AL., MICROBIOL MOL BIOL REV, vol. 67, 2003, pages 657 - 685
ARANEDA, R. C.KINI, A. D.FIRESTEIN, S.: "The molecular receptive range of an odorant receptor", NAT NEUROSCI, vol. 3, 2000, pages 1248 - 1255
ARANEDA, R. C.PETERLIN, Z.ZHANG, X.CHESLER, A.FIRESTEIN, S: "A pharmacological profile of the aldehyde receptor repertoire in rat olfactory epithelium", J PHYSIOL, vol. 555, 2004, pages 743 - 756
ARENZ, C. ET AL., NATURWISSENSCHAFTEN, vol. 90, 2003, pages 345 - 359
BITINAITE ET AL., PROC. NATL. ACAD. SCI. USA, vol. 95, 1998, pages 10570 - 5
BOZZA, T.FEINSTEIN, P.ZHENG, C.MOMBAERTS, P.: "Odorant receptor expression defines functional units in the mouse olfactory system", J NEUROSCI, vol. 22, 2002, pages 3033 - 3043
BUCK, L.AXEL, R.: "A novel multigene family may encode odorant receptors: a molecular basis for odor recognition", CELL, vol. 65, 1991, pages 175 - 187
BUTCHER, M. J.HERRE, M.LEY, K.GALKINA, E.: "Flow cytometry analysis of immune cells within murine aortas", J VIS EXP, 2011
CARROLL ET AL., GENETICS SOCIETY OF AMERICA, vol. 188, 2011, pages 773 - 782
CATHOMEN ET AL., MOL. THER., vol. 16, 2008, pages 1200 - 7
CERMAK ET AL., NUCL. ACIDS RES., vol. 39, 2011, pages 82
CLARK ADAM A. ET AL.: "Odorants specifically modulate chemotaxis and tissue retention of CD 4+ T cells via cyclic adenosine monophosphate induction", JOURNAL OF LEUKOCYTE BIOLOGY, vol. 100, no. 4, 2016, pages 699 - 709, XP055643875 *
COCHAIN, C. ET AL.: "Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis", CIRC RES, vol. 122, 2018, pages 1661 - 1674
DOENCH, J. ET AL., NATURE BIOTECHNOLOGY, vol. 32, no. 12, 2014, pages 1262 - 7
DOYON ET AL., NATURE METHODS, vol. 8, 2010, pages 74 - 79
ENSAN, S. ET AL.: "Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth", NAT IMMUNOL, vol. 17, 2016, pages 159 - 168
FERRER, I. ET AL.: "Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease", FRONT AGING NEUROSCI, vol. 8, 2016, pages 163
GEIBLER ET AL., PLOS ONE, vol. 6, 2011, pages 19509
GELIS LIAN ET AL.: "Functional expression of olfactory receptors in human primary melanoma and melanoma metastasis", EXPERIMENTAL DERMATOLOGY, vol. 26, no. 7, July 2017 (2017-07-01), pages 569 - 576, XP055643860 *
GINHOUX, F.JUNG, S.: "Monocytes and macrophages: developmental pathways and tissue homeostasis", NAT REV IMMUNOL, vol. 14, 2014, pages 392 - 404
GO, Y.NIIMURA, Y.: "Similar numbers but different repertoires of olfactory receptor genes in humans and chimpanzees", MOL BIOL EVOL, vol. 25, 2008, pages 1897 - 1907
GOMEZ PERDIGUERO, E. ET AL.: "Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors", NATURE, vol. 518, 2015, pages 547 - 551
GRAHAM, D. ET AL., GENOME BIOL, vol. 16, 2015, pages 260
GUO ET AL., J. MOL. BIO., vol. 200, 2010, pages 96
GUO ET AL., J. MOL. BIOI., vol. 400, 2010, pages 96
HANNON GJ, NATURE, vol. 418, 2002, pages 244 - 251
HOCKEMEYER ET AL., NATURE BIOTECH., vol. 29, 2011, pages 731 - 734
JACOBY, E.BOUHELAL, R.GERSPACHER, M.SEUWEN, K.: "The 7 TM G-protein-coupled receptor target family", CHEMMEDCHEM, vol. 1, 2006, pages 761 - 782
JOVANCEVIC NIKOLINA ET AL.: "Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor", BASIC RES CARDIOL., vol. 112, no. 2, 2017, pages 13, XP036483322, DOI: 10.1007/s00395-017-0600-y *
KANTER JENNY E. ET AL.: "Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1", PNAS, vol. 109, no. 12, 2012, pages 4353 - 4354, XP055643871 *
KARASAWA, T.TAKAHASHI, M.: "Role of NLRP3 Inflammasomes in Atherosclerosis", J ATHEROSCLER THROMB, vol. 24, 2017, pages 443 - 451
KATO, A.TOUHARA, K.: "Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization", CELL MOL LIFE SCI, vol. 66, 2009, pages 3743 - 3753
KELLEY, M. ET AL., J OF BIOTECHNOLOGY, vol. 233, 2016, pages 74 - 83
KIM, K. ET AL.: "Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models", CIRC, vol. 123, 2018, pages 1127 - 1142
KIM, PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 1156 - 1160
LEE, S. J.DEPOORTERE, I.HATT, H.: "Therapeutic potential of ectopic olfactory and taste receptors", NAT REV DRUG DISCOV, vol. 18, 2019, pages 116 - 138
LI JING JING ET AL.: "Activation of olfactory receptors on mouse pulmonary macrophages promotes monocyte chemotactic protein-1 production", PLOS ONE, vol. 8, 2013, pages e80148, XP055643852 *
LI, F. ET AL.: "Heterotrimeric G protein subunit Ggamma13 is critical to olfaction", J NEUROSCI, vol. 33, 2013, pages 7975 - 7984
LI, J. J. ET AL.: "Activation of olfactory receptors on mouse pulmonary macrophages promotes monocyte chemotactic protein-1 production", PLOS ONE, vol. 8, 2013, pages 80148
LI, Y. ET AL.: "Aldehyde recognition and discrimination by mammalian odorant receptors via functional group-specific hydration chemistry", ACS CHEM BIOL, vol. 9, 2014, pages 2563 - 2571
LIEBERMAN, PHARMACEUTICAL DOSAGE FORMS, vol. 1-3, 1992
LLOYD, THE ART, SCIENCE AND TECHNOLOGY OF PHARMACEUTICAL COMPOUNDING, 1999
MARTINON, F.BURNS, K.TSCHOPP, J.: "The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta", MOL CELL, vol. 10, 2002, pages 417 - 426
MILLER ET AL., NATURE BIOTECH, vol. 29, 2011, pages 149 - 53
MOHR, S. ET AL., FEBS JOURNAL, vol. 283, 2016, pages 3232 - 38
MOORE, K. J.SHEEDY, F. J.FISHER, E. A.: "Macrophages in atherosclerosis: a dynamic balance", NAT REV IMMUNOL, vol. 13, 2013, pages 709 - 721
MOSCOU ET AL., SCIENCE, vol. 326, 2009, pages 3501 - 12
PFAFFL, M. W.: "A new mathematical model for relative quantification in real-time RT-PCR", NUCLEIC ACIDS RES, vol. 29, 2001, pages 45
PICKAR, DOSAGE CALCULATIONS, 1999
PLOS ONE, vol. 9, no. 4, 2014
PLUZNICK, J. L. ET AL.: "Functional expression of the olfactory signaling system in the kidney", PROC NATL ACAD SCI, vol. 106, 2009, pages 2059 - 2064
PROVASI, NATURE MED, vol. 18, 2011, pages 807 - 815
RIDKER, P. M. ET AL.: "Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease", N ENGLJMED, vol. 377, 2017, pages 1119 - 1131
RIZZO, W. B.: "Fatty aldehyde and fatty alcohol metabolism: review and importance for epidermal structure and function", BIOCHIM BIOPHYS ACTA, vol. 1841, 2014, pages 377 - 389
ROSS, R.: "Atherosclerosis--an inflammatory disease", N ENGLJ MED, vol. 340, 1999, pages 115 - 126
ROUQUIER, S., BLANCHER, A. & GIORGI, D.: "The olfactory receptor gene repertoire in primates and mouse: evidence for reduction of the functional fraction in primates", PROC NATL ACAD SCI, vol. 97, 2000, pages 2870 - 2874
SAITO HARUMI ET AL.: "RTP family members induce functional expression of mammalian odorant receptors", CELL, vol. 119, 2 November 2004 (2004-11-02), pages 679 - 691, XP002577591, DOI: 10.1016/j.cell.2004.11.021 *
SAITO, H.KUBOTA, MROBERTS, R. W.CHI, Q.MATSUNAMI, H.: "RTP family members induce functional expression of mammalian odorant receptors", CELL, vol. 119, 2004, pages 679 - 691
See also references of EP3781173A4
SHARMA, R. ET AL.: "Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice", ELIFE, vol. 6, 2017
SILVA TEIXEIRA, C. S.CERQUEIRA, N. M.SILVA FERREIRA, A. C.: "Unravelling the Olfactory Sense: From the Gene to Odor Perception", CHEM SENSES, vol. 41, 2016, pages 105 - 121
SZCZEPEK ET AL., NATURE BIOTECH, vol. 25, 2007, pages 786 - 793
TORIKAI, BLOOD, vol. 122, 2013, pages 1341 - 1349
UKHANOV, K.BRUNERT, D.COREY, E. A.ACHE, B. W.: "Phosphoinositide 3-kinase-dependent antagonism in mammalian olfactory receptor neurons", J NEUROSCI, vol. 31, 2011, pages 273 - 280
UKHANOV, K.COREY, E. A.BRUNERT, D.KLASEN, K.ACHE, B. W.: "Inhibitory odorant signaling in Mammalian olfactory receptor neurons", J NEUROPHYSIOL, vol. 103, 2010, pages 1114 - 1122
WEBER LEA ET AL.: "Activation of odorant receptor in colorectal cancer cells leads to inhibition of cell proliferation and apoptosis", PLOS ONE., vol. 12, no. 3, 2017, pages e0172491, XP055643856 *
WINKELS, H. ET AL.: "Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry", CIRC RES, vol. 122, 2018, pages 1675 - 1688
WOLF STEFFEN ET AL.: "Dynamical Binding Modes Determine Agonistic and Antagonistic Ligand Effects in the Prostate-Specific G-Protein Coupled Receptor (PSGR", SCIENTIFIC REPORTS, vol. 7, 2017, pages 16007, XP055643849 *
WOLF, D.ZIRLIK, A.LEY, K.: "Beyond vascular inflammation--recent advances in understanding atherosclerosis", CELL MOL LIFE SCI, vol. 72, 2015, pages 3853 - 3869
WOOD ET AL., SCIENCE, vol. 333, 2011, pages 307
ZHANG Q. ET AL.: "CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer", CANCER RES., vol. 75, no. 20, 2015, pages 4312 - 4321, XP055643874 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2021105435A1 (en) 2019-11-28 2021-06-03 Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Prooxidative chain-transfer agents for use in the treatment of malignant tumour or infectious diseases
WO2021257905A3 (en) * 2020-06-17 2022-03-24 H. Lee Moffitt Cancer Center And Research Institute, Inc. Olfactory receptors for use as targets for antigen binding molecules to detect and treat cancer
WO2022128050A1 (en) * 2020-12-14 2022-06-23 Symrise Ag Medicament for fighting inflammation and pain
WO2023169996A1 (en) * 2022-03-07 2023-09-14 Fondazione Per L'istituto Oncologico Di Ricerca (Ior) Use of olfactory receptor or13a1 antagonists in the treatment of lymphomas
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