WO2018029336A1 - Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta - Google Patents

Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta Download PDF

Info

Publication number
WO2018029336A1
WO2018029336A1 PCT/EP2017/070419 EP2017070419W WO2018029336A1 WO 2018029336 A1 WO2018029336 A1 WO 2018029336A1 EP 2017070419 W EP2017070419 W EP 2017070419W WO 2018029336 A1 WO2018029336 A1 WO 2018029336A1
Authority
WO
WIPO (PCT)
Prior art keywords
subject
cells
ρραρνβ
activator
level
Prior art date
Application number
PCT/EP2017/070419
Other languages
English (en)
Inventor
Jacobus Neels
Anne-Sophie ROUSSEAU
Brigitte SIBILLE
Isabelle MOTHE-SATNEY
Joseph MURDACA
Paul Grimaldi
Original Assignee
INSERM (Institut National de la Santé et de la Recherche Médicale)
Universite Nice Sophia Antipolis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by INSERM (Institut National de la Santé et de la Recherche Médicale), Universite Nice Sophia Antipolis filed Critical INSERM (Institut National de la Santé et de la Recherche Médicale)
Publication of WO2018029336A1 publication Critical patent/WO2018029336A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70567—Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/90206—Oxidoreductases (1.) acting on the CH-CH group of donors (1.3)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91051—Acyltransferases other than aminoacyltransferases (general) (2.3.1)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/91045—Acyltransferases (2.3)
    • G01N2333/91051—Acyltransferases other than aminoacyltransferases (general) (2.3.1)
    • G01N2333/91057—Acyltransferases other than aminoacyltransferases (general) (2.3.1) with definite EC number (2.3.1.-)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the invention is in the field of immunology, particularly, the invention relates to methods for determining whether a subject was administered with an activator of the PPAR ⁇ / ⁇ pathway.
  • na ' ive T cells have a metabolically quiescent phenotype and use glucose, fatty acids, and amino acids to fuel oxidative phosphorylation to generate energy.
  • quiescent na ' ive T cells undergo a rapid proliferation phase which is associated with dramatically increased bioenergetic and biosynthetic demands.
  • activated T cells use aerobic glycolysis.
  • decreased glycolysis and increased lipid oxidation can favor the enrichment of long-lived CD8+ memory cells.
  • different T cell subsets have different metabolic signatures.
  • T cell proliferation whereas effector T cells are highly glycolytic, regulatory T cells have high lipid oxidation rates. It was demonstrated that by directly manipulating T-cell metabolism one can regulate T cell fate, suggesting that it may be possible to target metabolic pathways and mediators to control the formation of T-cell lineages or to suppress T-cell responses by blocking specific metabolic pathways essential for T-cell growth and proliferation (4, 5). Normally, committed lymphoid progenitors arise in the bone marrow and migrate to the thymus (for review on T cell development see (6)).
  • Thymocytes that express TCRs that bind self-peptide-MHC-class-I complexes become CD8+ single positive (SP) T cells, whereas those that express TCRs that bind self-peptide- MHC-class-II ligands become CD4+ SP T cells ( ⁇ T cells are not MHC restricted); these cells are then ready for export from the medulla to peripheral lymphoid sites.
  • SP single positive
  • DN4 thymocytes that have undergone a productive TCRP rearrangement show a proliferative burst (7). It is also during this stage that expression of the glucose transporter Glut-1 is highest, suggesting a high rate of glycolysis during this highly proliferative stage of T cell development (8).
  • PPARP Peroxisome proliferator-activated receptor ⁇
  • PPARP controls in myotubes, the expression of genes implicated in fatty acid (FA) uptake, handling and catabolism (Fatty Acid Translocase, FAT/CD36; Pyruvate dehydrogenase kinase 4, PDK4; and carnitine palmitoyltransferase 1A, CPT1A) and that in skeletal muscle, PPARP is upregulated in physiological situations characterized by increased lipido -oxidative metabolism, such as fasting or aerobic exercise training (10-12).
  • PPARp is present at the mRNA level in human CD4 and CD8+ T-cells and CD19+ B cells (13), and in peripheral blood T-cells (14).
  • PPARp is present at the mRNA level in human CD4 and CD8+ T-cells and CD19+ B cells (13), and in peripheral blood T-cells (14).
  • PPAR family of nuclear receptors in regulating fuel preference in developing T cells.
  • the present invention relates to a method for identifying whether a subject was administered with an activator of the PPARp/ ⁇ pathway comprising: i) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject; ii) comparing the expression determined at step i) with a predetermined reference value, and iii) concluding that the subject was administered with an activator of the PPARp/ ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step i) is higher than the predetermined reference value or concluding that the subject was not administered with an activator of the PPARp/ ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step i) is lower than the predetermined reference value.
  • the present invention is defined by the claims.
  • the inventors have investigated the effect of overexpressing PPARP on T cell biology in vivo by using mice that overexpress PPARP in a T cell specific manner. Using this transgenic mouse model, and also by systemic treatment of wild-type mice with a PPARP agonist, they have demonstrated that activation/overexpression of PPARP increases the fatty acid oxidation capacity of developing T cells, thereby inhibiting the proliferative burst at the DN4 stage. This leads to disruption of T cell development in the thymus with subsequent consequences for T cell populations in peripheral lymphoid organs. This study also suggests that stimulating lipid oxidation early on in T cell precursors will hamper their development into mature T cells.
  • the invention relates to a method for identifying whether a subject was administered with an activator of the ⁇ / ⁇ pathway comprising: i) quantifying the expression level of Acaa2, Acadvl and Cptl a in a blood sample obtained from said subject; ii) comparing the expression determined at step i) with a predetermined reference value, and iii) concluding that the subject was administered with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptl a determined at step i) is higher than the predetermined reference value or concluding that the subject was not administered with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptl a determined at step i) is lower than the predetermined reference value.
  • ⁇ / ⁇ refers to Peroxisome proliferator-activated receptors (PPARs) which are a family of ligand-activated nuclear receptors that play key roles in the regulation of cellular differentiation, development, metabolism and inflammation.
  • PPARs Peroxisome proliferator-activated receptors
  • the three different PPAR isoforms ( ⁇ , ⁇ or ⁇ , and ⁇ ) exhibit tissue-selective expression and are activated by different physiological and synthetic activators.
  • the major physiological functions of PPARs result from their activity as transcription factors, modulating the expression of specific target genes.
  • PPAR ⁇ / ⁇ is the predominant form in rodent and human skeletal muscle (SKM).
  • SBM rodent and human skeletal muscle
  • PPAR ⁇ / ⁇ controls transcription of several genes involved in metabolism, differentiation, inflammation, and proliferation.
  • PPAR ⁇ / ⁇ pathway refers to the signaling of molecules involved in the activation or inhibition of PPAR ⁇ / ⁇ .
  • the term “activator” refers to any compound, natural or not, that is able to increase the expression level of PPAR ⁇ / ⁇ or activate the PPAR ⁇ / ⁇ pathway.
  • the activator can also act as an agonist.
  • the term “agonist” refers to any compound natural or not that is able to bind to PPAR ⁇ / ⁇ and promotes PPAR ⁇ / ⁇ biological activity.
  • the terms “agonist” or “modulator” could be used interchangeably.
  • the activators include but are not limited to peptides, polypeptides, protein, nucleic acids such as aptamers, small organic molecules (natural or not). Particularly, the agonist of ⁇ / ⁇ is a small molecule.
  • small organic molecule refers to a molecule of a size comparable to those organic molecules generally used in pharmaceuticals.
  • small organic molecules range in size up to about 5000 Da, more preferably up to 2000 Da, and most preferably up to about 1000 Da.
  • the activator is a natural molecule such as unsaturated fatty acid; carbaprostacyclin or components of very low-density lipoprotein.
  • the activator is a synthetic molecule.
  • the activators of PPAR ⁇ / ⁇ are described in WO 2009078981.
  • the activator is GW501516, also known as Endurobol, which is a selective activator of ⁇ / ⁇ receptor (Sznaidman et al., 2003).
  • the activator is MBX-8025.
  • the activator is KD0310.
  • the activator is GW0742 (also known as GW610742).
  • the activator is L- 165041 (Berger et al., 1999).
  • the activator of ⁇ / ⁇ is a-lipoic acid (a-LA).
  • the activator of ⁇ / ⁇ pathway is Enalaprilat, also known as Enalapril.
  • the activator of ⁇ / ⁇ pathway corresponds to a natural or synthetic inhibitor of the JNK pathway which increases the expression level of ⁇ / ⁇ .
  • the activator of the ⁇ / ⁇ pathway is one of the compound as described in WO2010069833, WO2011151357, WO2011151358, WO2010097335, WO2010069833, WO2011151357, WO2008028860, WO2010046273, WO201213668, WO2013007676, WO2011071491, WO2006076595, WO2012145569, WO2004078756, WO2008095944, WO2010015803, WO2013074986, WO2013169793, WO2007125405, WO2012083092, WO2010108155, WO2001027268, WO2007031280, WO2011160653, WO2012048721, WO2013079213, WO2013091670, WO2010091310 or WO201417
  • the term "Acaa2” refers to acetyl-Coenzyme A acyltransferase 2, also known as 3-Ketoacyl-CoA thiolase is an enzyme that in humans is encoded by the ACAA2 gene and catalyzes the last step of the mitochondrial fatty acid beta oxidation spiral.
  • the naturally occurring human Acaa2 gene has a nucleotide sequence as shown in Genbank Accession number NM 006111.2 and the naturally occurring human Acaa2 protein has an aminoacid sequence as shown in Genbank Accession number NP 006102.2.
  • the murine nucleotide and amino acid sequences have also been described (Genbank Accession numbers NMJ77470.3 and NP_803421.1).
  • the term "Acadvl” refers to very long-chain specific acyl-CoA dehydrogenase, is an enzyme that in humans encoded by the ACADVL gene and catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid.
  • the naturally occurring human Acadvl gene has a nucleotide sequence as shown in Genbank Accession number NM 000018.3 and the naturally occurring human Acadvl protein has an aminoacid sequence as shown in Genbank Accession number NP 000009.1.
  • the murine nucleotide and amino acid sequences have also been described (Genbank Accession numbers NM 017366.3 and NP_059062.1).
  • Cptla refers to carnitine palmitoyltransferase 1A, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to 1-carnitine.
  • the naturally occurring human Cptla gene has a nucleotide sequence as shown in Genbank Accession number NM 001031847.2 and the naturally occurring human Cptl a protein has an aminoacid sequence as shown in Genbank Accession number NP 001027017.1.
  • the murine nucleotide and amino acid sequences have also been described (Genbank Accession numbers NM_013495.2 and NP_038523.2).
  • the term "expression level" corresponds to the expression level of each of the 3 genes.
  • the expression level of the 3 genes may be determined by any technology known by a person skilled in the art.
  • each gene expression level may be measured at the genomic and/or nucleic and/or protein level.
  • the expression level of gene is determined by measuring the amount of nucleic acid transcripts of each gene.
  • the expression level is determined by measuring the amount of each gene corresponding protein. The amount of nucleic acid transcripts can be measured by any technology known by a man skilled in the art.
  • the measure may be carried out directly on an extracted messenger RNA (mRNA) sample, or on retrotranscribed complementary DNA (cDNA) prepared from extracted mRNA by technologies well-known in the art.
  • mRNA messenger RNA
  • cDNA retrotranscribed complementary DNA
  • the amount of nucleic acid transcripts may be measured using any technology known by a man skilled in the art, including nucleic microarrays, quantitative PCR, microfluidic cards, and hybridization with a labelled probe.
  • the expression level is determined using quantitative PCR. Quantitative, or real-time, PCR is a well-known and easily available technology for those skilled in the art and does not need a precise description. Methods for determining the quantity of mR A are well known in the art.
  • the nucleic acid contained in the biological sample is first extracted according to standard methods, for example using lytic enzymes or chemical solutions or extracted by nucleic-acid-binding resins following the manufacturer's instructions.
  • the extracted mRNA is then detected by hybridization (e. g., Northern blot analysis) and/or amplification (e.g., RT-PCR).
  • hybridization e. g., Northern blot analysis
  • amplification e.g., RT-PCR
  • quantitative or semi-quantitative RT-PCR is performed. Real-time quantitative or semiquantitative RT-PCR is particularly advantageous.
  • LCR ligase chain reaction
  • TMA transcription- mediated amplification
  • SDA strand displacement amplification
  • NASBA nucleic acid sequence based amplification
  • Nucleic acids having at least 10 nucleotides and exhibiting sequence complementarity or homology to the mRNA of interest herein find utility as hybridization probes or amplification primers. It is understood that such nucleic acids need not be identical, but are typically at least about 80% identical to the homologous region of comparable size, more preferably 85% identical and even more preferably 90-95% identical. In certain embodiments, it will be advantageous to use nucleic acids in combination with appropriate means, such as a detectable label, for detecting hybridization. A wide variety of appropriate indicators are known in the art including, fluorescent, radioactive, enzymatic or other ligands (e. g. avidin/biotin).
  • Probes typically comprise single-stranded nucleic acids of between 10 to 1000 nucleotides in length, for instance of between 10 and 800, more preferably of between 15 and 700, typically of between 20 and 500.
  • Primers typically are shorter single- stranded nucleic acids, of between 10 to 25 nucleotides in length, designed to perfectly or almost perfectly match a nucleic acid of interest, to be amplified.
  • the probes and primers are "specific" to the nucleic acids they hybridize to, i.e. they preferably hybridize under high stringency hybridization conditions (corresponding to the highest melting temperature Tm, e.g., 50 % formamide, 5x or 6x SCC.
  • SCC is a 0.15 M NaCl, 0.015 M Na-citrate).
  • the nucleic acid primers or probes used in the above amplification and detection method may be assembled as a kit.
  • a kit includes consensus primers and molecular probes.
  • a kit also includes the components necessary to determine if amplification has occurred.
  • the kit may also include, for example, PCR buffers and enzymes; positive control sequences, reaction control primers; and instructions for amplifying and detecting the specific sequences.
  • the method of the invention comprises the steps of providing total R As extracted from a biological samples and subjecting the R As to amplification and hybridization to specific probes, more particularly by means of a quantitative or semi-quantitative RT-PCR.
  • the expression level is determined by DNA chip analysis.
  • DNA chip or nucleic acid microarray consists of different nucleic acid probes that are chemically attached to a substrate, which can be a microchip, a glass slide or a microsphere- sized bead.
  • a microchip may be constituted of polymers, plastics, resins, polysaccharides, silica or silica-based materials, carbon, metals, inorganic glasses, or nitrocellulose.
  • Probes comprise nucleic acids such as cDNAs or oligonucleotides that may be about 10 to about 60 base pairs.
  • a biological sample from a test subject optionally first subjected to a reverse transcription, is labelled and contacted with the microarray in hybridization conditions, leading to the formation of complexes between target nucleic acids that are complementary to probe sequences attached to the microarray surface.
  • the labelled hybridized complexes are then detected and can be quantified or semi-quantified. Labelling may be achieved by various methods, e.g. by using radioactive or fluorescent labelling.
  • Many variants of the microarray hybridization technology are available to the man skilled in the art (see e.g. the review by Hoheisel, Nature Reviews, Genetics, 2006, 7:200- 210).
  • the term "subject" refers to any mammals, such as a rodent, a feline, a canine, an equidae and a primate. Particularly, in the present invention, the subject is a human. In a particular embodiment, the subject suffers from a disorder selected from the group consisting of:
  • inflammatory diseases such as Crohn's disease, irritable bowel syndrome (IBS), systemic lupus erythematous (SLE), nephritis;
  • IBS irritable bowel syndrome
  • SLE systemic lupus erythematous
  • auto-immune diseases such as rheumatoid arthritis, ystemic lupus erythematosus (lupus), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis;
  • cardiovascular diseases such as heart failure, kidney diseases (e.g. renal failure, nephritis, etc.) hypertension, pulmonary hypertension, cirrhosis, arteriosclerosis, pulmonary emphysema, pulmonary oedema; stroke, brain ischemia, myocardial impairment in sepsis;
  • kidney diseases e.g. renal failure, nephritis, etc.
  • hypertension pulmonary hypertension, cirrhosis, arteriosclerosis, pulmonary emphysema, pulmonary oedema
  • stroke brain ischemia, myocardial impairment in sepsis
  • metabolic disease such as obesity, diabetes, anorexia, hyperphagia, polyphagia, hypercholesterolemia, hyperglyceridemia, hyperlipemia; various types of dementia such as senile dementia, cerebrovascular dementia, dementia due to genealogical denaturation degenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), dementia resulting from infectious diseases (e.g. delayed virus infections such as Creutzfeldt-Jakob disease), dementia associated with endocrine diseases, metabolic diseases, or poisoning (e.g. hypothyroidism, vitamin B12 deficiency, alcoholism, poisoning caused by various drugs, metals, or organic compounds), dementia caused by tumors (e.g. brain tumor), and dementia due to traumatic diseases (e.g. chronic subdural hematoma), depression, hyperactive child syndrome (microencephalopathy), disturbance of consciousness, anxiety disorder, schizophrenia, phobia;
  • dementia such as obesity, diabetes, anorexia, hyperphagia,
  • muscles disorders such as skeletal muscle atrophy which is associated with bed rest, corticosteroid use, denervation, chronic renal failure, limb immobilization, neuromuscular disorders, sarcopenia of aging, and arthritis (WO2015035171); cancer, such as cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • cancer such as cancer cells from the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lympho epithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo- alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acid
  • blood sample means any blood sample derived from the subject.
  • Peripheral blood is preferred, and mononuclear cells (PBMCs) are the preferred cells.
  • PBMC peripheral blood mononuclear cells
  • unfractionated PBMC refers to whole PBMC, i.e. to a population of white blood cells having a round nucleus, which has not been enriched for a given sub-population.
  • these cells can be extracted from whole blood using Ficoll, a hydrophilic polysaccharide that separates layers of blood, with the PBMC forming a cell ring under a layer of plasma.
  • PBMC can be extracted from whole blood using a hypotonic lysis which will preferentially lyse red blood cells. Such procedures are known to the expert in the art.
  • predetermined reference value refers to a threshold value or a cut-off value.
  • a threshold value can be determined experimentally, empirically, or theoretically.
  • a threshold value can also be arbitrarily selected based upon the existing experimental and/or clinical conditions, as would be recognized by a person of ordinary skilled in the art. For example, retrospective measurement in properly banked historical subject samples may be used in establishing the predetermined reference value. The threshold value has to be determined in order to obtain the optimal sensitivity and specificity according to the function of the test and the benefit/risk balance (clinical consequences of false positive and false negative).
  • the optimal sensitivity and specificity can be determined using a Receiver Operating Characteristic (ROC) curve based on experimental data.
  • ROC Receiver Operating Characteristic
  • the full name of ROC curve is receiver operator characteristic curve, which is also known as receiver operation characteristic curve. It is mainly used for clinical biochemical diagnostic tests.
  • ROC curve is a comprehensive indicator that reflects the continuous variables of true positive rate (sensitivity) and false positive rate (1 -specificity). It reveals the relationship between sensitivity and specificity with the image composition method.
  • a series of different cut-off values are set as continuous variables to calculate a series of sensitivity and specificity values. Then sensitivity is used as the vertical coordinate and specificity is used as the horizontal coordinate to draw a curve. The higher the area under the curve (AUC), the higher the accuracy of diagnosis.
  • AUC area under the curve
  • the point closest to the far upper left of the coordinate diagram is a critical point having both high sensitivity and high specificity values.
  • the AUC value of the ROC curve is between 1.0 and 0.5. When AUO0.5, the diagnostic result gets better and better as AUC approaches 1. When AUC is between 0.5 and 0.7, the accuracy is low. When AUC is between 0.7 and 0.9, the accuracy is moderate.
  • This algorithmic method is preferably done with a computer.
  • Existing software or systems in the art may be used for the drawing of the ROC curve, such as: MedCalc 9.2.0.1 medical statistical software, SPSS 9.0, ROCPOWER.SAS, DESIGNROC.FOR, MULTIREADER POWER.SAS, CREATE-ROC.SAS, GB STAT VIO.O (Dynamic Microsystems, Inc. Silver Spring, Md., USA), etc.
  • the invention relates to a method for identifying whether a subject was administered with an activator of the PPARp/ ⁇ pathway comprising: i) quantifying the level of ⁇ T cells in a blood sample obtained from said subject; ii) quantifying the level of ⁇ T cells in a blood sample obtained from said subject; iii) calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii); iv) comparing the ratio determined at step iii) with a predetermined reference value, and v) concluding that the subject was administered with an activator of the PPARp/ ⁇ pathway when the ratio determined at step iii) is lower than the predetermined reference value or concluding that the subject was not administered with an activator of the PPARp/ ⁇ pathway when the ratio determined at step iv) is higher than the predetermined reference value
  • ⁇ T cells refers to T cells which express a T cell receptor (TCR) that is composed of a- and ⁇ -protein chains.
  • TCR T cell receptor
  • the majority (>80%) of all CD3+ T cells in a normal, healthy person are ⁇ T cells.
  • TCRs are associated with the invariant CD3 molecule that distinguishes T cells from B cells and all other types of immune cells.
  • the majority of ⁇ T cells recognize the antigen in a so-called major histocompatibility complex (MHC) molecules-restricted fashion.
  • MHC major histocompatibility complex
  • MHC-I MHC class I
  • MHC-I MHC class II
  • TCRs on CD4+ ⁇ T cells recognize MHC-II-peptide complexes
  • TCRs on CD8+ ⁇ T cells recognize MHC-I-peptide complexes.
  • ⁇ T cells refers to T cells which express a T cell receptor (TCR) that is composed of ⁇ - and ⁇ -protein chains. They are a distinct subset of CD3+ T cells featuring TCRs that are encoded by Vy- and ⁇ -gene segments (Morita et al, 2000; Carding and Egan, 2002). In humans, V01+-TCR chain expressing ⁇ T cells (V61+ T cells) predominate in epithelial or epithelia-associated/mucosal tissues of the skin, airways, digestive and urogenital tracts, and several internal organs, and constitute a minor fraction ( ⁇ 20%) of ⁇ T cells in peripheral blood.
  • TCR T cell receptor
  • the TCRs of ⁇ 1+ T cells recognize lipid antigens presented by MHC-related CD1 molecules.
  • ⁇ T cells make up 2-10% of total CD3+ T cells, and the majority (>80%) of peripheral blood ⁇ T cells are Vy2V02+-TCR chain-expressing ⁇ T cells (V 2V82 + ⁇ T cells) (Morita et al., 2000; Carding and Egan, 2002).
  • the major subset of ⁇ T cells in human peripheral blood does not express CD4 or CD8 and its TCRs do not require MHC-restriction for antigen recognition.
  • the ⁇ T cells or ⁇ T cells are quantified by cell sorting, more particularly by Fluorescence-activated cell sorting (FACS).
  • FACS Fluorescence-activated cell sorting
  • cells are incubated with a fluorescently labelled antibody which recognizes a polypeptide present on the surface on the target cells population.
  • the cells are then forced into a small nozzle of a cell sorter one at a time. They are then scanned by a fluorescence laser, separated according to their fluorescence and the target population can be collected.
  • the quantification of these cells is performed by contacting the blood sample with a binding partner (e.g antibody) for a cell marker of said cells.
  • a binding partner e.g antibody
  • the quantification of these cells is performed by contacting the blood sample with several binding partners (e.g antibody) specific for following cell surface markers CD3, CD4, TCRc ⁇ ⁇ , CD44, CD62L, CD25, CD44 and CD8.
  • binding partners e.g antibody
  • binding partners are coupled with fluorescent agents known in the art, such as fluorescein, isothiocyanate, phycoerythrin etc.
  • the method according to the invention is suitable for determining whether a subject responds to a treatment with an activator of the PPAR ⁇ / ⁇ pathway. More particularly, the method of the invention is suitable to determine whether a treatment with an activator of PPAR ⁇ / ⁇ pathway increases the level of biomarkers such as Acaa2, Acadvl and Cptla or decrease the ratio of the level of ⁇ T cells to the level of ⁇ T cells quantified in a blood sample.
  • biomarkers such as Acaa2, Acadvl and Cptla
  • the ratio of the level of ⁇ T cells to the level of ⁇ T cells quantified in a blood sample Typically, firstly, the skilled man will measure the biomarker levels in blood sample before starting ⁇ / ⁇ pathway agonist treatment which corresponds to a reference value. Secondly, the skilled man will measure the biomarker levels in blood sample during the treatment. When the biomarkers level during treatment are increased compared to the biomarker level before treatment, it is indicated that the treatment was activating the ⁇ /
  • the invention relates to a method for determining whether a subject responds to a treatment with an activator of the ⁇ / ⁇ pathway comprising: i) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject before the treatment; ii) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject during the treatment; iii) comparing the expression determined at step ii) with a predetermined reference value, and iv) concluding that the subject responds to a treatment with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step ii) is higher than the predetermined reference value or concluding that the subject will not achieve a response to a treatment with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step i
  • the term “respond” refers to the response to a treatment of the subject suffering from a disorder. Typically such treatment induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. Accordingly, the survival time of the subject is increased with said treatment.
  • the term “respond” refers to the ability of an activator of the ⁇ / ⁇ pathway to an improvement of the pathological symptoms, thus, the subject presents a clinical improvement compared to the subject who does not receive the treatment. The said subject is considered as a "responder" to the treatment.
  • not respond refers to a subject who does not present any clinical improvement to the treatment with an activator of the ⁇ / ⁇ pathway treatment. This subject is considered as a “non-responder” to the treatment. Accordingly, the subject as considered “non-responder” has a particular monitoring in the therapeutic regimen.
  • the term "subject” refers to a human. Particularly, the subject suffers from one of the disorders as described above.
  • the "predetermined reference value” refers to the level of biomarkers determined before the treatment with an activator of the ⁇ / ⁇ pathway.
  • the present invention relates to a method for determining whether a subject responds to a treatment with an activator of the ⁇ / ⁇ pathway comprising: i) quantifying the level of ⁇ T cells in a blood sample obtained from said subject before the treatment; ii) quantifying the level of ⁇ T cells in a blood sample obtained from said subject before the treatment; iii) calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii); iv) calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii) during the treatment; v) comparing the ratio determined at step iv) with a predetermined reference value, and vi) concluding that the subject responds to the treatment with an activator of the ⁇ / ⁇ pathway when the ratio determined at step iv) is lower than the predetermined reference value or concluding that the subject does not respond to the treatment with
  • the method according to the invention is useful for a physician to monitor the subjects treated with an activator of the ⁇ / ⁇ pathway and to change the therapeutic regimen when the subject is determined as non-responder.
  • the invention relates to a method of treating a subject in need thereof comprising the following steps: i) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject before the treatment; ii) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject during the treatment; iii) comparing the expression determined at step ii) with a predetermined reference value, iv) concluding that the subject will achieve a response to a treatment with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step ii) is higher than the predetermined reference value or concluding that the subject will not achieve a response to a treatment with an activator of the ⁇ / ⁇ pathway when the expression level of Acaa2, Acadvl and Cptla determined at step ii) is lower than the predetermined reference value;
  • treating refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]).
  • the term "subject” refers to a human. Particularly, the subject suffers from one of the disorders as described above.
  • a “therapeutically effective amount” is intended for a minimal amount of active agent which is necessary to impart therapeutic benefit to a subject.
  • a “therapeutically effective amount” to a subject is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. It will be understood that the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the "predetermined reference value" refers to the level of biomarkers determined before the treatment with an activator of the ⁇ / ⁇ pathway.
  • anti-inflammatory drugs refers to a substance that reduces inflammation or swelling.
  • the anti-inflammatory drugs are well known in the art and including, but not limited to non-steroidal anti-inflammatory drugs (e.g aspirin, ibuprofen, naproxen etc); aminosalicylates (e.g. azulfidine); corticosteroids etc
  • anti-diabetic drugs refers to a substance used in diabetes to treat diabetes mellitus by lowering glucose levels in the blood. This kind of drugs are well known in the art and including, but not limited to Metformin, Thiazolidinediones, Exenatide; Liraglutide; Taspoglutide; Lixisenatide etc.
  • chemotherapeutic agents refers to chemical compounds that are effective in inhibiting tumor growth.
  • examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues);
  • calicheamicin especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33 : 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyr
  • paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • antihormonal agents that act to regulate or inhibit honnone action on tumors
  • anti- estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • immunotherapeutic agents refers to a compound, composition or treatment that indirectly or directly enhances, stimulates or increases the body's immune response against cancer cells and/or that decreases the side effects of other anticancer therapies.
  • immunotherapeutic agents include, but are not limited to, cytokines, cancer vaccines, monoclonal antibodies and non- cytokine adjuvants.
  • the immunotherapeutic treatment may consist of administering the subject with an amount of immune cells (T cells, NK, cells, dendritic cells, B cells).
  • the immunotherapeutic agent is an immune checkpoint inhibitor.
  • immune checkpoint inhibitor refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins.
  • Checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD1 with its ligands PDL1 and PDL2 (Pardoll, Nature Reviews Cancer 12: 252-264, 2012). These proteins are responsible for co-stimulatory or inhibitory interactions of T-cell responses.
  • Immune checkpoint proteins regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.
  • the immune checkpoint inhibitor is an antibody selected from the group consisting of anti-CTLA4 antibodies (e.g. Ipilimumab), anti-PDl antibodies (e.g. Nivolumab, Pembrolizumab), anti-PDLl antibodies, anti-TIM3 antibodies, anti-LAG3 antibodies, anti- B7H3 antibodies, anti-B7H4 antibodies, anti-BTLA antibodies, and anti-B7H6 antibodies.
  • anti-CTLA4 antibodies e.g. Ipilimumab
  • anti-PDl antibodies e.g. Nivolumab, Pembrolizumab
  • anti-PDLl antibodies anti-TIM3 antibodies
  • anti-LAG3 antibodies anti- B7H3 antibodies
  • anti-B7H4 antibodies anti-BTLA antibodies
  • anti-B7H6 antibodies anti-B7H6 antibodies.
  • anti-CTLA-4 antibodies are described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,
  • One anti-CTLA-4 antibody is tremelimumab, (ticilimumab, CP-675,206).
  • the anti- CTLA-4 antibody is ipilimumab (also known as 10D1, MDX-D010) a fully human monoclonal IgG antibody that binds to CTLA-4.
  • Another immune checkpoint protein is programmed cell death 1 (PD-1). Examples of PD-1 and PD-L1 blockers are described in US Patent Nos.
  • the PD-1 blockers include anti-PD-Ll antibodies.
  • the PD-1 blockers include anti-PD-1 antibodies and similar binding proteins such as nivolumab (MDX 1106, BMS 936558, ONO 4538), a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2; lambrolizumab (MK- 3475 or SCH 900475), a humanized monoclonal IgG4 antibody against PD-1; CT-011 a humanized antibody that binds PD-1 ; AMP-224 is a fusion protein of B7-DC; an antibody Fc portion; BMS-936559 (MDX- 1105-01) for PD-L1 (B7-H1) blockade.
  • nivolumab MDX 1106, BMS 936558, ONO 4538
  • a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2
  • immune-checkpoint inhibitors include lymphocyte activation gene-3 (LAG-3) inhibitors, such as IMP321, a soluble Ig fusion protein (Brignone et al, 2007, J. Immunol. 179:4202-4211).
  • Other immune-checkpoint inhibitors include B7 inhibitors, such as B7-H3 and B7-H4 inhibitors.
  • the anti-B7-H3 antibody MGA271 (Loo et al, 2012, Clin. Cancer Res. July 15 (18) 3834).
  • TIM3 T-cell immunoglobulin domain and mucin domain 3) inhibitors (Fourcade et al, 2010, J. Exp. Med. 207:2175-86 and Sakuishi et al, 2010, J.
  • the immunotherapeutic treatment consists of an adoptive immunotherapy, as described by Nicholas P. Restifo, Mark E. Dudley and Steven A. Rosenberg ("Adoptive immunotherapy for cancer: harnessing the T cell response, Nature Reviews Immunology, Volume 12, April 2012).
  • adoptive immunotherapy the patient's circulating lymphocytes, or tumor-infiltrated lymphocytes, are isolated in vitro, activated by lymphokines such as IL-2 and readministered (Rosenberg et al, 1988; 1989).
  • the activated lymphocytes are most preferably be the patient's own cells that were earlier isolated from a blood sample and activated (or "expanded") in vitro.
  • radiotherapeutic agents is intended to refer to any radio therapeutic agent known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation.
  • the radiotherapeutic agent can be an agent such as those administered in brachytherapy or radionuclide therapy.
  • Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies, and/or another radiotherapy.
  • the invention relates to a method of treating a subject in need thereof comprising the following steps: i) quantifying the level of ⁇ T cells in a blood sample obtained from said subject before the treatment with an activator of the ⁇ / ⁇ pathway ; ii) quantifying the level of ⁇ T cells in a blood sample obtained from said subject before the treatment with an activator of the ⁇ / ⁇ pathway; iii) calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii); iv calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii) during the treatment; v) comparing the ratio determined at step iv) with a predetermined reference value; vi) concluding that the subject will achieve a response to the treatment with an activator of the ⁇ / ⁇ pathway when the ratio determined at step iv) is lower than the predetermined reference value or concluding
  • the method according to the invention is suitable for identifying whether a high level athlete subject was administered with an activator of ⁇ / ⁇ .
  • the World Anti-Doping Agency (WAD A) has classified activators of ⁇ / ⁇ to the prohibited list of substances.
  • WADA World Anti-Doping Agency
  • the invention relates to a method for identifying whether an high level athlete subject was administered with an activator of ⁇ / ⁇ comprising: i) quantifying the expression level of Acaa2, Acadvl and Cptla in a blood sample obtained from said subject; ii) comparing the expression determined at step i) with a predetermined reference value, and iii) concluding that the subject was administered with an activator of ⁇ / ⁇ when the expression level of Acaa2, Acadvl and Cptla determined at step i) is higher than the predetermined reference value or concluding that the subject was not administered with an activator of ⁇ / ⁇ when the expression level of Acaa2, Acadvl and Cptla determined at step i) is lower than the predetermined reference value.
  • the term "high level athlete subject” refers to rodent, a feline, a canine, an equidae and a primate.
  • the subject is a human. More particularly, a human who trains to compete in sports or exercises involving physical strength, speed, or endurance. The athlete has a natural aptitude for physical activities and participates to sport events (e.g national or international level competitions).
  • the high level athlete subject is a person who practices at least one sport selected from the group consisting of: race bike, run, karate, swimming, athletics (e.g competitive running, jumping, throwing or walking).
  • the high level athlete subject belongs to the family Equidae.
  • the high level athlete subject is a horse, typically, a horse which participates to horses racing.
  • the invention relates to a method for identifying whether an high level athlete subject was administered with an activator of the ⁇ / ⁇ pathway comprising: i) quantifying the level of ⁇ T cells in a blood sample obtained from said high level athlete subject ; ii) quantifying the level of ⁇ T cells in a blood sample obtained from said high level athlete subject ; iii) calculating the ratio of the level of ⁇ T cells quantified at step i) to the level of ⁇ T cells quantified at step ii); iv) comparing the ratio determined at step iii) with a predetermined reference value, and v) concluding that the an high level athlete subject was administered with an activator of ⁇ / ⁇ pathway when the ratio determined at step iii) is lower than the predetermined reference value or concluding that the high level athlete subject was not administered with an activator of ⁇ / ⁇ pathway when the ratio determined at step iv) is higher than the predetermined reference value.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 PPARji is functional in T cells and its activation adversely affects thymic T cell development.
  • A Relative Acaa2, Acadvl, and Cptla mRNA levels in in vitro activated primary mouse CD4+ T cells treated for 48 hrs with 3 ⁇ GW0742 ( ⁇ agonist) or 0.1% DMSO (vehicle).
  • B Relative Cptla mRNA levels in thymus or lymph node tissue from mice treated for 48 hrs in vivo with GW0742 (0.3 mg/kg/day LP.) or vehicle (equivalent volume of DMSO). Data is normalized to DMSO control.
  • C Total thymic cell counts from mice that received identical treatment as in (B).
  • Data is pooled from 5 independent experiments (A) or from tissues obtained from 6 mice per treatment group (B-E), with flow plots shown in (D) being representative of latter treatment groups.
  • Data shown in bar graphs (A-C,E) are expressed as mean ⁇ s.e.m. *P ⁇ 0.05 when compared to DMSO control (Mann- Whitney test).
  • FIG. 1 Consequences of impaired T cell development in Tg T-PPARp mice for peripheral T cell populations. Quantification of various T cell populations in spleen (A) and lymph nodes (B).
  • Figure 3 Development of ⁇ T cells is impaired in Tg T-PPARp mice while ⁇ T cell production is unaffected. Data shown in bar graphs are expressed as mean ⁇ s.e.m. *P ⁇ 0.05 when compared to control (Mann- Whitney test).
  • FIG. 4 Impaired T cell development observed in vivo in Tg T-PPARp mice can be reproduced in vitro in the OP9-DL1 co-culture model.
  • A Expansion of control (open circles) vs Tg ⁇ - ⁇ (closed circles) DN2/DN3 thymocytes after 3, 5, 7, and 12 days of co-culture with OP9-DL1 cells. Data are presented as number of cells per well (xl04), with 104 DN2/DN3 cells seeded on OP9-DL1 cells in a 24-well format at day 0.
  • FIG. 5 Treatment with GW0742 increases Cptla mRNA levels in lymphoid tissues and blood. Mice were treated for a period of 6 weeks with the ⁇ agonist GW0742 (3 mg/kg/day) supplemented in their food. Cptla mRNA levels in different lymphoid tissues and blood was measured by qPCR. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001.
  • CAG-Stop- ⁇ mice carrying a transgene containing the modified chicken ⁇ -actin promoter with the CMV/IE enhancer (CAG promoter) driving ⁇ -IRES- Hygromycin chimeric mRNA expression under CRE-mediated recombination of a transcriptional Stop fragment, were described previously (11). Both strains are on the C57BL/6J background and were crossed to obtain double transgenic animals that overexpress ⁇ specifically in T cells (Lck-Cre/CAG-Stop- ⁇ mice). For convenience these double transgenic animals are referred to as Tg ⁇ - ⁇ mice.
  • the isolated CD4+ cells were cultured at a concentration of 4 x 105 cells/well in a 48-well plate in RPMI containing 10% FCS, 100 units/ml penicillin/streptomycin, and 50 ⁇ 2-mercaptoethanol.
  • Cells were treated with 3 ⁇ GW0742 or 0.1% DMSO (vehicle) and activated with anti-CD3/anti-CD28 beads (Dynabeads mouse T-activator CD3/CD28, Invitrogen) following instructions provided by the manufacturer.
  • the activated primary CD4+ cells were harvested and used directly for mRNA extraction and real-time quantitative PCR analysis. RNA extraction and quantitative real-time PCR.
  • Total R A was extracted from cells or tissues with Triz 1 reagent following the supplier's protocol (Invitrogen).
  • total RNA (1 ⁇ g) was reverse-transcribed using a QuantiTect Reverse Transcription Kit (Qiagen) on a Qcyclerll.
  • Quantitative PCR was done using SYBR Premix Ex Taq (Tli RNase H Plus) (Ozyme) on a StepOne machine (Life Technologies). The mRNA levels of all genes reported were normalized to 36B4 transcript levels. Primer sequences are available upon request.
  • RNA 0.5 ⁇ g was reversetranscribed using the RT2 First Strand reagents as part of the array kit per the manufacturer's instructions and qPCR was performed on a StepOne machine following detection protocols recommended by SA Biosciences. Data was analyzed using the excel spreadsheet provided online on the manufacturer's website.
  • Thymi, spleens and lymph nodes were harvested from control and Tg-T-PPARP mice and converted into single cell suspensions in phosphate-buffered saline (PBS), pH 7.2, containing 0.5% fetal calf serum (FCS) and 2mM EDTA, using a gentleMACS Dissociator and appropriate gentleMACS C tubes by following the protocols provided by the manufacturer (Miltenyi Biotec). Splenocyte single cell suspensions were subsequently depleted of red blood cells with RBC lysis buffer (Sigma).
  • PBS phosphate-buffered saline
  • FCS fetal calf serum
  • 2mM EDTA 2mM EDTA
  • the resulting single cell suspensions were incubated with Fc Block (anti-mouse CD16/CD32 monoclonal antibody, BD Biosciences) for 15 min at 4°C before staining with fluorescently labeled primary antibodies for 20 min at 4°C in PBS, 0.5% BSA.
  • Fc Block anti-mouse CD16/CD32 monoclonal antibody, BD Biosciences
  • CD3-fluorescein isothiocyanate CD3- phycoerythrin, CD4-allophycocyanin, TCRP-phycoerythrin-Cy7, TCRy5- phycoerythrin, CD44-phycoerythrin-Cy7, CD62L-fluorescein isothiocyanate, CD25 -phycoerythrin, and CD44-phycoerythrin FACS antibodies were purchased from eBioscience. CD8-Peridinin chlorophyll antibody was from BD Biosciences.
  • OP9-DL1 co-cultures The DN2/DN3 thymocytes used in co-cultures were isolated from thymocyte cell suspensions by labeling them using anti-CD25-phycoerythrin (PE) antibody and subsequently purifying them using an anti-PE multisort kit (Miltenyi Biotec). The resulting cell preparation still contained contaminating CD4+ cells, so the anti-PE microbeads were released from the cells using the MultiSort Release Reagent from the kit to allow for a second labeling with CD4 (L3T4) microbeads to deplete CD4+ cells.
  • PE anti-CD25-phycoerythrin
  • DN2/DN3 thymocytes isolated from control and Tg T-PPARP mice were added at a concentration of 104 cells/well to 24- well plates that were seeded the day before with 104 OP9-DL1 cells in Opti-MEM medium supplemented with GlutaMAX (Gibco), 10% FCS, 100 units/ml penicillin/streptomycin, and 50 ⁇ 2-mercaptoethanol.
  • Interleukin 7 R&D Systems
  • PPARp activation in vivo leads to a reduction in thymocyte numbers.
  • PPARP is functional in T cells, and that its activation induces genes implicated in fatty acid metabolism.
  • a PPARP agonist 3 ⁇ GW0742
  • vehicle 0.1 % DMSO
  • T cell specific overexpression of PPARp disrupts T cell development in the thymus.
  • Tg T-PPARP transgenic mouse model
  • Cre-recombinase which's expression is driven by the lymphocyte protein tyrosine kinase (Lck) promoter that is active early on during T cell development, to remove a stop cassette that is flanked by LoxP sites, allowing transcription of the downstream PPARP transgene. Thymic size, weight and cell counts were reduced in these Tg T-PPARP mice compared to littermate control (Lck- Cre+/-) mice.
  • Lck lymphocyte protein tyrosine kinase
  • Flow cytometry profiles, based on surface expression of CD4 and CD8 showed that, like with the in vivo PPARP agonist treatment, there was a significant reduction in the percentage of DP thymocytes in the Tg T-PPARP mice compared to littermate control mice (67.4 ⁇ 4.2% vs 79.4 ⁇ 2.1%). Furthermore, the percentage of double negative (DN; CD4-CD8-) thymocytes had significantly more than doubled in the Tg T-PPARP mice compared to littermate control mice (19.9 ⁇ 3.7% vs 7.5 ⁇ 1.4%).
  • mice has consequences for T cell populations in peripheral lymphoid organs, we analysed the T cell populations in spleen, lymph nodes, and blood from Tg ⁇ - ⁇ and littermate control mice. Total cell counts already show a reduction in total number of spleen and lymph node cells in these lymphoid organs when comparing Tg ⁇ - ⁇ with littermate control mice. Flow cytometry data shows that the percentage of CD3+ cells is decreased significantly in all three tissues in the Tg ⁇ - ⁇ mice compared to littermate control mice.
  • CD4 and CD8 expression on these CD3+ cells we observed a trend towards a decrease in percentages of both CD4+CD8- and CD4-CD8+ cells in most cases, accompanied by a significant 2.5- to 4-fold increase in the percentage of CD4-CD8- cells in all three lymphoid tissues examined from Tg ⁇ - ⁇ mice compared to littermate control mice.
  • CD4+ and CD8+ T cells largely consist of cells expressing the ⁇ T cell receptor (TCR), and cells expressing the ⁇ TCR, for the large majority, are neither expressing CD4 nor CD8. Therefore, we anticipated that the decrease in CD4+ and CD8+ cells in peripheral lymphoid tissues is illustrative of a decrease in ⁇ T cells, while the unchanged numbers of CD4-CD8- cells would suggest that ⁇ T cell production is not affected. We confirm that TCR ⁇ + cells in these lymphoid tissues indeed, for the large majority, consist of CD4+ and CD8+ cells, with only between 1 to 4% of cells being CD4-CD8-.
  • TCR ⁇ T cell receptor
  • TCRy5+ cells from these lymphoid tissues mostly ( ⁇ 80%>) consist of CD4-CD8- cells.
  • TCR ⁇ + and TCRy5+ populations as gated on CD3+ cells, in the different lymphoid tissues, a significant decrease in the percentage of TCR ⁇ + cells in Tg T-PPAR ⁇ compared to littermate control mice in all tissues is observed.
  • the percentage of TCRy5+ cells is increased by 4- to 6-fold in these tissues when comparing Tg T-PPAR ⁇ to littermate control mice.
  • CD44-CD62L+ naive CD62L+
  • memory CD44+CD62L+
  • effector CD44+CD62L- CD4+ or CD8+ T cell populations in peripheral lymphoid tissues.
  • the percentage of naive T cells is consistently lower and the percentage of effector T cells is consistently higher in all three lymphoid tissues from Tg T-PPARP mice compared to littermate control mice, regardless whether they are CD4+ or CD8+.
  • DN1 CD25-CD44+
  • DN2 CD25+CD44+
  • DN3 CD25+CD44-
  • DN4 CD25-CD44-
  • Tg T-PPARp mice The phenotype observed in Tg T-PPARp mice can be reproduced in vitro in the OP9-DL1 coculture model.
  • DN2 and DN3 thymocytes express CD25 to isolate those populations from thymi from control and Tg ⁇ - ⁇ mice by positive selection using magnetic beads.
  • This approach resulted in the isolation of cell populations that were enriched in DN thymocytes ( ⁇ 90-95%) consisting mostly (90%) of a mix of DN2 (16-18%) and DN3 (73-75%o) thymocytes.
  • these cell preparations still contained a significant amount (3-9%) of SP4 thymocytes we performed a second phase of enrichment by depleting the cells of CD4+ cells, again using a magnetic bead approach.
  • control DN2/DN3 progeny include a higher percentage of SP4 cells (43.5 ⁇ 1.0%) than progeny from Tg ⁇ - ⁇ DN2/DN3 thymocytes (30.9 ⁇ 0.6%). Almost no SP8 cells had developed in these cocultures, as previously already observed under similar co-culture conditions (16, 17). The percentage of DP cells derived from the different DN2/DN3 thymocyte populations doesn't differ significantly.
  • the majority of DN progeny derived from Tg ⁇ - ⁇ DN2/DN3 thymocytes remains at the DN3 stage (74.2 ⁇ 1.4%), with only 23.5 ⁇ 1.6% of newly transitioned DN4 thymocytes.
  • mice were treated for a period of 6 weeks with the PPAR ⁇ agonist GW0742 (3 mg/kg/day) supplemented in their food.
  • Treatment with GW0742 increases Cptla mRNA levels in lymphoid tissues and blood (Fig.5).
  • mice either underwent no exercise (sedentary control), a single bout of exercise on a treadmill (5° inclination, 35 cm/s during 1 hour), or 8 weeks of regular treadmill exercise (4 weeks adaptation with 3 exercises/week, followed by 3 weeks of 5 exercises/week, and 1 last week with 3 exercises).
  • Inventors have demonstrated that a single bout or regular exercise does not affect Cptla mRNA levels in lymphoid tissues and blood (Fig.6).
  • PPAR ⁇ has been shown to play a protective role in a growing list of inflammatory conditions (e.g. septic and non-septic shock, inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE)), varying from acute to chronic inflammatory diseases and including several autoimmune diseases (9). Furthermore, PPAR ⁇ has been implicated in both the innate and adaptive immune system. In almost all the inflammatory disease models studied, PPAR ⁇ activation or overexpression leads to a decrease in inflammation, and deletion of PPARP leads to an aggravation of the inflammatory state. As a consequence, PPARP presents an interesting therapeutic target in a large variety of inflammatory conditions.
  • septic and non-septic shock e.g. septic and non-septic shock, inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE)
  • EAE experimental autoimmune encephalomyelitis
  • PPARP can regulate inflammatory gene expression is by interacting with the p65 subunit of NFDB, a key transcriptional regulator of inflammation (19). Furthermore, two reports identified PPARP as a crucial signalling molecule controlling the phenotypic switch between pro -inflammatory Ml and anti-inflammatory M2 macrophages (20, 21). Except for these reports on macrophages, very little is known regarding the function of PPARD in other key inflammatory/immune cell types. Except for some reports demonstrating a role for PPARP in the T cell-mediated mouse EAE model (22-25), the study of the role of PPARP in T cells is still in its infancy.
  • PPARP agonists are not yet in clinical use, human studies have been performed to test the efficacy of two compounds, GW501516 and MBX-8025, providing very encouraging findings for the treatment of metabolic disorders in dyslipidemic obese individuals (30-34). Although no adverse effects were reported in these human studies, further investigations with larger groups of individuals and longer period of treatment are required to fully establish the safety of these PPARP agonists. Furthermore, GW501516 is available from online retailers, often under the name of Endurobol, and the compound has been added since 2009 to the prohibited list of substances by the World Anti-Doping Agency (www.wada-ama.org).
  • PPARdelta is a type 1 IFN target gene and inhibits apoptosis in T cells. J Invest Dermatol

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Analytical Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Urology & Nephrology (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Virology (AREA)
  • Biophysics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Food Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Les inventeurs ont examiné l'effet de surexpression de PPARβ sur la biologie des cellules T in vivo à l'aide de souris surexprimant PPARβ de manière spécifique des cellules T. À l'aide de ce modèle de souris transgénique, et également par traitement systémique de souris de type sauvage par un agoniste de PPARβ, les inventeurs ont démontré que l'activation / la surexpression de PPARβ augmentait la capacité des cellules T en développement à oxyder les acides gras, inhibant ainsi l'explosion proliférative de l'étape DN4. En conséquence, la présente invention concerne une méthode permettant d'identifier si un patient a reçu un activateur de la voie PPARβ/δ, et consistant à : i) quantifier les niveaux d'expression d'Acaa2, Acadvl et Cpt1a dans un échantillon sanguin provenant dudit patient ; ii) comparer chaque niveau expression déterminé à l'étape i) à une valeur de référence prédéterminée, et iii) conclure que le sujet a reçu un activateur de la voie PPARβ/δ lorsque les niveaux d'expression d'Acaa2, Acadvl et Cpt1a déterminés à l'étape i) sont supérieurs aux valeurs de référence prédéterminées.
PCT/EP2017/070419 2016-08-12 2017-08-11 Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta WO2018029336A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP16306050 2016-08-12
EP16306050.2 2016-08-12

Publications (1)

Publication Number Publication Date
WO2018029336A1 true WO2018029336A1 (fr) 2018-02-15

Family

ID=56853561

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/070419 WO2018029336A1 (fr) 2016-08-12 2017-08-11 Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta

Country Status (1)

Country Link
WO (1) WO2018029336A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112703039A (zh) * 2018-09-14 2021-04-23 洛桑大学 用于调节调节性t细胞和抑制肿瘤生长的方法

Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5855887A (en) 1995-07-25 1999-01-05 The Regents Of The University Of California Blockade of lymphocyte down-regulation associated with CTLA-4 signaling
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6207157B1 (en) 1996-04-23 2001-03-27 The United States Of America As Represented By The Department Of Health And Human Services Conjugate vaccine for nontypeable Haemophilus influenzae
WO2001027268A2 (fr) 1999-10-12 2001-04-19 University Of Lausanne Inhibiteurs peptidiques, a permeabilite cellulaire, du mecanisme de transduction du signal de jnk
WO2003042402A2 (fr) 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents modulant l'activite de cellules immunes et procedes d'utilisation associes
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
WO2004078756A2 (fr) 2003-03-06 2004-09-16 Eisai Co., Ltd. Inhibiteurs des jun-kinases (jnk)
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
WO2006076595A1 (fr) 2005-01-13 2006-07-20 Signal Pharmaceuticals, Llc Aminopurines a substitution haloaryle, compositions les contenant, et methodes de traitement associees haloaryl
WO2007031280A2 (fr) 2005-09-12 2007-03-22 Xigen S.A. Inhibiteurs peptidiques permeables aux cellules de la voie de transduction de signal jnk
WO2007125405A2 (fr) 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008028860A1 (fr) 2006-09-08 2008-03-13 F. Hoffmann-La Roche Ag Modulateurs de kinases à base de benzotriazole
WO2008095944A1 (fr) 2007-02-06 2008-08-14 Eisai R&D Management Co. Ltd. Dérivés de 7-azaindole et leur utilisation dans l'inhibition de c-jun n-terminal kinase
WO2008156712A1 (fr) 2007-06-18 2008-12-24 N. V. Organon Anticorps dirigés contre le récepteur humain de mort programmée pd-1
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
WO2009078981A2 (fr) 2007-12-13 2009-06-25 Sri International Ligands ppar-delta et leurs procédés d'utilisation
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
WO2010015803A1 (fr) 2008-08-05 2010-02-11 Eisai R & D Management Co. Ltd Dérivés de diazaindole et leur utilisation dans l’inhibition de kinase c-jun n-terminale
WO2010036959A2 (fr) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations
WO2010046273A2 (fr) 2008-10-22 2010-04-29 F. Hoffmann-La Roche Ag Inhibiteurs pyrimidinylpyridone de jnk
WO2010069833A1 (fr) 2008-12-19 2010-06-24 F. Hoffmann-La Roche Ag Dérivés pyrimidin-2-ylamino et leur utilisation dans le traitement d'une inflammation
WO2010089411A2 (fr) 2009-02-09 2010-08-12 Universite De La Mediterranee Anticorps pd-1 et anticorps pd-l1 et leurs utilisations
WO2010091310A1 (fr) 2009-02-06 2010-08-12 Elan Pharmaceuticals, Inc. Inhibiteurs de l'enzyme jun n-terminal kinase
WO2010097335A1 (fr) 2009-02-24 2010-09-02 F. Hoffmann-La Roche Ag Imidazo[1,2-a]pyridines comme modulateurs de la jnk
WO2010108155A1 (fr) 2009-03-20 2010-09-23 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de conductance transmembranaire de la mucoviscidose
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2011071491A1 (fr) 2009-12-09 2011-06-16 Signal Pharmaceuticals, Llc Isotopologues du 4-[9-(tétrahydrofuran-3-yl)-8-(2,4,6-trifluorophénylamino)-9h-purin-2-ylamino]cyclohexan-1-ol
WO2011082400A2 (fr) 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
WO2011151358A1 (fr) 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Dérivés de 2-amino-pyrimidine utiles en tant qu'inhibiteurs de la jnk
WO2011151357A1 (fr) 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
WO2011159877A2 (fr) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques
WO2011160653A1 (fr) 2010-06-21 2011-12-29 Xigen S.A. Nouvelles molécules inhibant jnk
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
WO2012013668A1 (fr) 2010-07-27 2012-02-02 Fondazione Bruno Kessler Diffractomètre à rayons x amélioré et procédé d'installation dudit diffractomètre à rayons x amélioré
WO2012048721A1 (fr) 2010-10-14 2012-04-19 Xigen S.A. Utilisation d'inhibiteurs peptidiques, aptes à pénétrer dans les cellules, de la voie de transduction du signal jnk pour le traitement de maladies oculaires inflammatoires chroniques ou non-chroniques
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
WO2012083092A2 (fr) 2010-12-16 2012-06-21 Sanford-Burnham Medical Research Institute Composés bidentates en tant qu'inhibiteurs de la kinase
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2012145569A1 (fr) 2011-04-22 2012-10-26 Signal Pharmaceuticals, Llc Diaminocarboxamidepyrimidines et diaminocarbonitrilepyrimidines substituées, compositions de celles-ci et procédés de traitement à l'aide de celles-ci
WO2013007676A1 (fr) 2011-07-12 2013-01-17 F. Hoffmann-La Roche Ag Composés d'aminométhyl-quinolone
WO2013074986A1 (fr) 2011-11-17 2013-05-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs de la kinase c-jun-n-terminale (jnk)
WO2013079213A1 (fr) 2011-11-30 2013-06-06 Xigen Inflammation Ltd. Utilisation d'inhibiteurs peptidiques pouvant pénétrer dans des cellules de la voie de transduction de signal jnk pour le traitement du syndrome de sécheresse oculaire
WO2013091670A1 (fr) 2011-12-21 2013-06-27 Xigen S.A. Nouvelles molécules inhibitrices de jnk pour le traitement de diverses maladies
WO2013169793A2 (fr) 2012-05-09 2013-11-14 Ipierian, Inc. Procédés et compositions pour des protéinopathies tdp-43
WO2014170706A1 (fr) 2013-04-15 2014-10-23 Università Degli Studi Di Bari Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk
WO2015035171A1 (fr) 2013-09-09 2015-03-12 High Point Pharmaceuticals, Llc Utilisation d'un agoniste de ppar-delta pour le traitement d'une amyotrophie

Patent Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5855887A (en) 1995-07-25 1999-01-05 The Regents Of The University Of California Blockade of lymphocyte down-regulation associated with CTLA-4 signaling
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6207157B1 (en) 1996-04-23 2001-03-27 The United States Of America As Represented By The Department Of Health And Human Services Conjugate vaccine for nontypeable Haemophilus influenzae
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
US6984720B1 (en) 1999-08-24 2006-01-10 Medarex, Inc. Human CTLA-4 antibodies
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
WO2001027268A2 (fr) 1999-10-12 2001-04-19 University Of Lausanne Inhibiteurs peptidiques, a permeabilite cellulaire, du mecanisme de transduction du signal de jnk
WO2003042402A2 (fr) 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents modulant l'activite de cellules immunes et procedes d'utilisation associes
US7488802B2 (en) 2002-12-23 2009-02-10 Wyeth Antibodies against PD-1
WO2004078756A2 (fr) 2003-03-06 2004-09-16 Eisai Co., Ltd. Inhibiteurs des jun-kinases (jnk)
WO2006076595A1 (fr) 2005-01-13 2006-07-20 Signal Pharmaceuticals, Llc Aminopurines a substitution haloaryle, compositions les contenant, et methodes de traitement associees haloaryl
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2007031280A2 (fr) 2005-09-12 2007-03-22 Xigen S.A. Inhibiteurs peptidiques permeables aux cellules de la voie de transduction de signal jnk
WO2007125405A2 (fr) 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008028860A1 (fr) 2006-09-08 2008-03-13 F. Hoffmann-La Roche Ag Modulateurs de kinases à base de benzotriazole
WO2008095944A1 (fr) 2007-02-06 2008-08-14 Eisai R&D Management Co. Ltd. Dérivés de 7-azaindole et leur utilisation dans l'inhibition de c-jun n-terminal kinase
WO2008156712A1 (fr) 2007-06-18 2008-12-24 N. V. Organon Anticorps dirigés contre le récepteur humain de mort programmée pd-1
WO2009078981A2 (fr) 2007-12-13 2009-06-25 Sri International Ligands ppar-delta et leurs procédés d'utilisation
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
WO2010015803A1 (fr) 2008-08-05 2010-02-11 Eisai R & D Management Co. Ltd Dérivés de diazaindole et leur utilisation dans l’inhibition de kinase c-jun n-terminale
WO2010036959A2 (fr) 2008-09-26 2010-04-01 Dana-Farber Cancer Institute Anticorps anti-pd-1, pd-l1, et pd-l2 humains et leurs utilisations
WO2010046273A2 (fr) 2008-10-22 2010-04-29 F. Hoffmann-La Roche Ag Inhibiteurs pyrimidinylpyridone de jnk
US8217149B2 (en) 2008-12-09 2012-07-10 Genentech, Inc. Anti-PD-L1 antibodies, compositions and articles of manufacture
WO2010069833A1 (fr) 2008-12-19 2010-06-24 F. Hoffmann-La Roche Ag Dérivés pyrimidin-2-ylamino et leur utilisation dans le traitement d'une inflammation
WO2010091310A1 (fr) 2009-02-06 2010-08-12 Elan Pharmaceuticals, Inc. Inhibiteurs de l'enzyme jun n-terminal kinase
WO2010089411A2 (fr) 2009-02-09 2010-08-12 Universite De La Mediterranee Anticorps pd-1 et anticorps pd-l1 et leurs utilisations
WO2010097335A1 (fr) 2009-02-24 2010-09-02 F. Hoffmann-La Roche Ag Imidazo[1,2-a]pyridines comme modulateurs de la jnk
WO2010108155A1 (fr) 2009-03-20 2010-09-23 Vertex Pharmaceuticals Incorporated Modulateurs du régulateur de conductance transmembranaire de la mucoviscidose
WO2011066342A2 (fr) 2009-11-24 2011-06-03 Amplimmune, Inc. Inhibition simultanée de pd-l1/pd-l2
WO2011071491A1 (fr) 2009-12-09 2011-06-16 Signal Pharmaceuticals, Llc Isotopologues du 4-[9-(tétrahydrofuran-3-yl)-8-(2,4,6-trifluorophénylamino)-9h-purin-2-ylamino]cyclohexan-1-ol
WO2011082400A2 (fr) 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulateurs du récepteur immunosuppresseur pd-1 et procédés d'utilisation de ceux-ci
WO2011151358A1 (fr) 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Dérivés de 2-amino-pyrimidine utiles en tant qu'inhibiteurs de la jnk
WO2011151357A1 (fr) 2010-06-04 2011-12-08 F. Hoffmann-La Roche Ag Inhibiteurs de la jnk
WO2011159877A2 (fr) 2010-06-18 2011-12-22 The Brigham And Women's Hospital, Inc. Anticorps di-spécifiques anti-tim-3 et pd-1 pour immunothérapie dans des états pathologiques immuns chroniques
WO2011160653A1 (fr) 2010-06-21 2011-12-29 Xigen S.A. Nouvelles molécules inhibant jnk
WO2011161699A2 (fr) 2010-06-25 2011-12-29 Aurigene Discovery Technologies Limited Composés modulateurs de l'immunosuppression
WO2012013668A1 (fr) 2010-07-27 2012-02-02 Fondazione Bruno Kessler Diffractomètre à rayons x amélioré et procédé d'installation dudit diffractomètre à rayons x amélioré
WO2012048721A1 (fr) 2010-10-14 2012-04-19 Xigen S.A. Utilisation d'inhibiteurs peptidiques, aptes à pénétrer dans les cellules, de la voie de transduction du signal jnk pour le traitement de maladies oculaires inflammatoires chroniques ou non-chroniques
WO2012083092A2 (fr) 2010-12-16 2012-06-21 Sanford-Burnham Medical Research Institute Composés bidentates en tant qu'inhibiteurs de la kinase
WO2012145569A1 (fr) 2011-04-22 2012-10-26 Signal Pharmaceuticals, Llc Diaminocarboxamidepyrimidines et diaminocarbonitrilepyrimidines substituées, compositions de celles-ci et procédés de traitement à l'aide de celles-ci
WO2013007676A1 (fr) 2011-07-12 2013-01-17 F. Hoffmann-La Roche Ag Composés d'aminométhyl-quinolone
WO2013074986A1 (fr) 2011-11-17 2013-05-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs de la kinase c-jun-n-terminale (jnk)
WO2013079213A1 (fr) 2011-11-30 2013-06-06 Xigen Inflammation Ltd. Utilisation d'inhibiteurs peptidiques pouvant pénétrer dans des cellules de la voie de transduction de signal jnk pour le traitement du syndrome de sécheresse oculaire
WO2013091670A1 (fr) 2011-12-21 2013-06-27 Xigen S.A. Nouvelles molécules inhibitrices de jnk pour le traitement de diverses maladies
WO2013169793A2 (fr) 2012-05-09 2013-11-14 Ipierian, Inc. Procédés et compositions pour des protéinopathies tdp-43
WO2014170706A1 (fr) 2013-04-15 2014-10-23 Università Degli Studi Di Bari Composés à base de galloyl benzamide utilisés en tant que modulateurs de jnk
WO2015035171A1 (fr) 2013-09-09 2015-03-12 High Point Pharmaceuticals, Llc Utilisation d'un agoniste de ppar-delta pour le traitement d'une amyotrophie

Non-Patent Citations (61)

* Cited by examiner, † Cited by third party
Title
"Genbank", Database accession no. NM _001031847.2
"Genbank", Database accession no. NM 000018.3
"Genbank", Database accession no. NM 006111.2
"Genbank", Database accession no. NM_013495.2
"Genbank", Database accession no. NM_017366.3
"Genbank", Database accession no. NM_177470.3
"GENBANK", Database accession no. NP _038523.2
"Genbank", Database accession no. NP 000009.1
"Genbank", Database accession no. NP 001027017.1
"Genbank", Database accession no. NP 006102.2
"GENBANK", Database accession no. NP_059062.1
"GENBANK", Database accession no. NP_803421.1
AGNEW CHEM INTL. ED. ENGL., vol. 33, 1994, pages 183 - 186
AL YACOUB N; ROMANOWSKA M; KRAUSS S; SCHWEIGER S; FOERSTER J: "PPARdelta is a type 1 IFN target gene and inhibits apoptosis in T cells", J INVEST DERMATOL, vol. 128, no. 8, 2008, pages 1940 - 1949
B GROSS ET AL: "Generation and characterization of a humanized PPAR[delta] mouse model", BRITISH JOURNAL OF PHARMACOLOGY, vol. 164, no. 1, 5 August 2011 (2011-08-05), pages 192 - 208, XP055335357, ISSN: 0007-1188, DOI: 10.1111/j.1476-5381.2011.01359.x *
BAYS HE ET AL.: "MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin", J CLIN ENDOCRINOL METAB, vol. 96, no. 9, 2011, pages 2889 - 2897, XP008152800, DOI: doi:10.1210/jc.2011-1061
BRIGNONE ET AL., J. IMMUNOL., vol. 179, 2007, pages 4202 - 4211
CHOI YJ ET AL.: "Effects of the PPAR-delta agonist MBX-8025 on atherogenic dyslipidemia", ATHEROSCLEROSIS, vol. 220, no. 2, 2012, pages 470 - 476, XP002677651, DOI: doi:10.1016/J.ATHEROSCLEROSIS.2011.10.029
DUNN SE ET AL.: "Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity", THE JOURNAL OF EXPERIMENTAL MEDICINE, vol. 207, no. 8, 2010, pages 1599 - 1608
FOURCADE ET AL., J. EXP. MED., vol. 207, 2010, pages 2175 - 86
GIRROIR EE ET AL.: "Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 371, no. 3, 2008, pages 456 - 461
GRIMALDI PA: "Metabolic and nonmetabolic regulatory functions of peroxisome proliferator-activated receptor beta", CURR OPIN LIPIDOL, vol. 21, no. 3, 2010, pages 186 - 191
HOHEISEL, NATURE REVIEWS, GENETICS, vol. 7, 2006, pages 200 - 210
HOIST D ET AL.: "Nutritional regulation and role of peroxisome proliferator-activated receptor delta in fatty acid catabolism in skeletal muscle", BIOCHIM BIOPHYS ACTA, vol. 1633, no. 1, 2003, pages 43 - 50, XP004434940, DOI: doi:10.1016/S1388-1981(03)00071-4
ISABELLE MOTHE-SATNEY ET AL: "A role for Peroxisome Proliferator-Activated Receptor Beta in T cell development", SCIENTIFIC REPORTS, vol. 6, 29 September 2016 (2016-09-29), pages 34317, XP055334937, DOI: 10.1038/srep34317 *
KANAKASABAI S ET AL.: "Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Thl) and Thl7 responses in experimental allergic encephalomyelitis", IMMUNOLOGY, 2010
KANAKASABAI S; WALLINE CC; CHAKRABORTY S; BRIGHT JJ: "PPARdelta deficient mice develop elevated Thl/Thl7 responses and prolonged experimental autoimmune encephalomyelitis", BRAIN RES, vol. 1376, 2011, pages 101 - 112
KANG K ET AL.: "Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity", CELL METAB, vol. 7, no. 6, 2008, pages 485 - 495
KOCH U; RADTKE F: "Mechanisms of T cell development and transformation", ANNU REV CELL DEV BIOL, vol. 27, 2011, pages 539 - 562
KUNG J; HENRY RR: "Thiazolidinedione safety", EXPERT OPIN DRUG SAF, vol. 11, no. 4, 2012, pages 565 - 579
LEE CH ET AL.: "Transcriptional repression of atherogenic inflammation: modulation by PPARdelta", SCIENCE, vol. 302, no. 5644, 2003, pages 453 - 457, XP009174273, DOI: doi:10.1126/science.1087344
LOCHNER M; BEROD L; SPARWASSER T: "Fatty acid metabolism in the regulation of T cell function", TRENDS IN IMMUNOLOGY, vol. 36, no. 2, 2015, pages 81 - 91
LOO ET AL., CLIN. CANCER RES., vol. 15, no. 18, July 2012 (2012-07-01), pages 3834
LUQUET S ET AL.: "Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability", FASEB J, vol. 17, no. 15, 2003, pages 2299 - 2301
MACINTYRE AN ET AL.: "The glucose transporter Glutl is selectively essential for CD4 T cell activation and effector function", CELL METABOLISM, vol. 20, no. 1, 2014, pages 61 - 72
MARINA KEMMERER ET AL: "AMP-Activated Protein Kinase Interacts with the Peroxisome Proliferator-Activated Receptor Delta to Induce Genes Affecting Fatty Acid Oxidation in Human Macrophages", PLOS ONE, vol. 10, no. 6, 22 June 2015 (2015-06-22), pages e0130893, XP055335112, DOI: 10.1371/journal.pone.0130893 *
MICHALEK RD ET AL.: "Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets", J IMMUNOL, vol. 186, no. 6, 2011, pages 3299 - 3303
NEELS JG; GRIMALDI PA: "Physiological functions of peroxisome proliferator-activated receptor beta", PHYSIOLOGICAL REVIEWS, vol. 94, no. 3, 2014, pages 795 - 858
NICHOLAS P. RESTIFO; MARK E. DUDLEY; STEVEN A. ROSENBERG: "Adoptive immunotherapy for cancer: harnessing the T cell response", NATURE REVIEWS IMMUNOLOGY, vol. 12, April 2012 (2012-04-01), XP055034896, DOI: doi:10.1038/nri3191
ODEGAARD JI ET AL.: "Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance", CELL METAB, vol. 7, no. 6, 2008, pages 496 - 507
OOI EM; WATTS GF; SPRECHER DL; CHAN DC; BARRETT PH: "Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity", J CLIN ENDOCRINOL METAB, vol. 96, no. 10, 2011, pages E1568 - 1576
O'SULLIVAN D; PEARCE EL: "Targeting T cell metabolism for therapy", TRENDS IN IMMUNOLOGY, vol. 36, no. 2, 2015, pages 71 - 80, XP055322656, DOI: doi:10.1016/j.it.2014.12.004
PALMER CS; OSTROWSKI M; BALDERSON B; CHRISTIAN N; CROWE SM: "Glucose metabolism regulates T cell activation, differentiation, and functions", FRONT IMMUNOL, vol. 6, 2015, pages 1
PARDOLL, NATURE REVIEWS CANCER, vol. 12, 2012, pages 252 - 264
PENIT C; LUCAS B; VASSEUR F: "Cell expansion and growth arrest phases during the transition from precursor (CD4-8-) to immature (CD4+8+) thymocytes in normal and genetically modified mice", JOURNAL OF IMMUNOLOGY, vol. 154, no. 10, 1995, pages 5103 - 5113
POLAK PE ET AL.: "Protective effects of a peroxisome proliferator-activated receptorbeta/ delta agonist in experimental autoimmune encephalomyelitis", J NEUROIMMUNOL, vol. 168, no. 1- 2, 2005, pages 65 - 75, XP027673097
RISERUS U ET AL.: "Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men", DIABETES, vol. 57, no. 2, 2008, pages 332 - 339, XP055090241, DOI: doi:10.2337/db07-1318
ROUSSEAU AS ET AL.: "alpha-Lipoic acid up-regulates expression of peroxisome proliferator-activated receptor beta in skeletal muscle: involvement of the JNK signalling pathway", FASEB JOURNAL : OFFICIAL PUBLICATION OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY, vol. 30, no. 3, 2016, pages 1287 - 1299
SABA I; KOSAN C; VASSEN L; MOROY T: "IL-7R-dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz- 1", BLOOD, vol. 117, no. 12, 2011, pages 3370 - 3381
SAKUISHI ET AL., J. EXP. MED., vol. 207, 2010, pages 2187 - 94
SCHMITT TM; CIOFANI M; PETRIE HT; ZUNIGA-PFLUCKER JC: "Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions", THE JOURNAL OF EXPERIMENTAL MEDICINE, vol. 200, no. 4, 2004, pages 469 - 479, XP003011553, DOI: doi:10.1084/jem.20040394
SCHMITT TM; ZUNIGA-PFLUCKER JC: "Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro", IMMUNITY, vol. 17, no. 6, 2002, pages 749 - 756, XP002338760, DOI: doi:10.1016/S1074-7613(02)00474-0
SCHOTE AB; TURNER JD; SCHILTZ J; MULLER CP: "Nuclear receptors in human immune cells: expression and correlations", MOL IMMUNOL, vol. 44, no. 6, 2007, pages 1436 - 1445, XP005664761, DOI: doi:10.1016/j.molimm.2006.04.021
SHI J; PETRIE HT: "Activation kinetics and off-target effects of thymus-initiated cre transgenes", PLOS ONE, vol. 7, no. 10, 2012, pages e46590
SHI LZ ET AL.: "HIF1 alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells", J EXP MED, vol. 208, no. 7, 2011, pages 1367 - 1376
SPRECHER DL ET AL.: "Triglyceride:high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor delta agonist", ARTERIOSCLER THROMB VASC BIOL, vol. 27, no. 2, 2007, pages 359 - 365, XP002495025, DOI: doi:10.1161/01.ATV.0000252790.70572.0c
T. ADHIKARY ET AL: "The transcriptional PPAR / network in human macrophages defines a unique agonist-induced activation state", NUCLEIC ACIDS RESEARCH, vol. 43, no. 10, 26 May 2015 (2015-05-26), pages 5033 - 5051, XP055335367, ISSN: 0305-1048, DOI: 10.1093/nar/gkv331 *
TANAKA T ET AL: "Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 100, no. 26, 23 December 2003 (2003-12-23), pages 15924 - 15929, XP002983797, ISSN: 0027-8424, DOI: 10.1073/PNAS.0306981100 *
TOSHIYA TANAKA ET AL: "PPAR[beta]/[delta] activation of CD300a controls intestinal immunity", SCIENTIFIC REPORTS, vol. 4, 24 June 2014 (2014-06-24), XP055335860, DOI: 10.1038/srep05412 *
YANG H; YOUM YH; DIXIT VD: "Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution", JOURNAL OF IMMUNOLOGY, vol. 183, no. 5, 2009, pages 3040 - 3052
YOUM YH ET AL.: "Thiazolidinedione treatment and constitutive-PPARgamma activation induces ectopic adipogenesis and promotes age-related thymic involution", AGING CELL, vol. 9, no. 4, 2010, pages 478 - 489

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112703039A (zh) * 2018-09-14 2021-04-23 洛桑大学 用于调节调节性t细胞和抑制肿瘤生长的方法

Similar Documents

Publication Publication Date Title
US12016876B2 (en) Micro-RNAs and compositions comprising same for the treatment and diagnosis of serotonin-, adrenalin-, noradrenalin-, glutamate-, and corticotropin-releasing hormone- associated medical conditions
CN106715695B (zh) 用于治疗和诊断的微rna和包含所述微rna的组合物
WO2009086306A1 (fr) Modulateurs de la toxicité d'alpha-synucléine
US20220107323A1 (en) Methods and compositions for identifying whether a subject suffering from a cancer will achieve a response with an immune-checkpoint inhibitor
US20190345500A1 (en) Methods and pharmaceutical compositions for modulating stem cells proliferation or differentiation
WO2018029336A1 (fr) Méthodes visant à déterminer si un patient a reçu un activateur de la voie de ppar bêta/delta
KR101973027B1 (ko) 뇌종양의 진단 및 치료에서의 nupr1의 용도
Cutolo et al. Identification and quantification of selected inflammatory genes modulated by leflunomide and prednisone treatment in early rheumatoid arthritis patients
CN106554962B (zh) 过表达gpr160的癌症的预防、诊断和治疗
CN117205198B (zh) 丹参酚酸c(sac)作为新型抗衰老药物原料在细胞衰老、肿瘤治疗与延长寿命中的应用
CN117205193B (zh) 丹参酚酸a(saa)作为新型抗衰老药物原料在细胞衰老、肿瘤治疗与延长寿命中的应用
CN117205197B (zh) 丹参酚酸b(sab)作为新型抗衰老药物原料在细胞衰老、肿瘤治疗与延长寿命中的应用
Jeon et al. Expression of Tcf-1 mRNA and surface TCR-CD3 complexes are reduced during apoptosis of T cells.
US20230416838A1 (en) Methods and compositions for predicting and treating uveal melanoma
US20230072528A1 (en) Methods for discontinuing a treatment with a tyrosine kinase inhibitor (tki)
US20210080467A1 (en) Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors
KR20240066997A (ko) 항암 면역치료제 반응성 예측방법
WO2021037978A1 (fr) Procédés pour le diagnostic et le traitement du cancer
Tourniaire et al. Chemokine Expression in Inflamed Adipose Tissue Is Mainly Mediated

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17749491

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17749491

Country of ref document: EP

Kind code of ref document: A1