WO1996040232A1 - Oral tolerance in skin diseases presenting with t-cell mediated inflammation - Google Patents
Oral tolerance in skin diseases presenting with t-cell mediated inflammation Download PDFInfo
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- WO1996040232A1 WO1996040232A1 PCT/US1996/010384 US9610384W WO9640232A1 WO 1996040232 A1 WO1996040232 A1 WO 1996040232A1 US 9610384 W US9610384 W US 9610384W WO 9640232 A1 WO9640232 A1 WO 9640232A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
- A61K2039/541—Mucosal route
- A61K2039/542—Mucosal route oral/gastrointestinal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to methods and compositions for treatment of skin diseases presenting with T-cell mediated or T-cell dependent inflammation. More particularly, this invention relates to methods and compositions for treating such diseases through orally (or mucosally) induced tolerance resulting in suppression of inflammation.
- oral tolerance orally induced tolerance
- autoantigens and bystander antigens defined below
- T-cell mediated autoimmune disease in both animals and humans: Thompson, H.S.G. et al. Clin. Exp. Immunol . , 64:581-586, 1986; Nagler-Anderson, C. et al. Proc. Nat'l .
- Autoantigen is any substance or a portion thereof normally found within a mammal that, in an autoimmune disease, becomes the primary (or a primary) target of attack by the immunoregulatory system.
- the term also includes antigenic substances that induce conditions having the characteristics of an autoimmune disease when administered to mammals.
- the term includes peptidic subclasses consisting essentially of immunodominant epitopes or immunodominant epitope regions of autoantigens. Immunodominant epitopes or regions in induced autoimmune conditions are fragments of an autoantigen that can be used instead of the entire autoantigen to induce the disease.
- immunodominant epitopes or regions are fragments of antigens specific to the tissue or organ under autoimmune attack and recognized by a substantial percentage (e.g. a majority though not necessarily an absolute majority) of autoimmune attack T-cells.
- “Bystander antigen” or “bystander” is a protein, protein fragment, peptide, glycoprotein, or any other immunogenic substance (i.e. a substance capable of eliciting an immune response) that (i) is, or is derived from, a component specific to (or primarily found in) the organ or tissue under autoimmune attack; and (ii) upon oral or enteral administration elicits regulatory (suppressor) T-cells (which can be of the CD4+ or CD8+ type) that are targeted to the organ or tissue under attack where they cause at least one antigen- nonspecific immunosuppressive factor or immunoregulatory cytokine (such as TGF-3, IL-4 or IL-10) to be released and thereby suppress immune attack cells that contribute to autoimmune destruction.
- regulatory (suppressor) T-cells which can be of the CD4+ or CD8+ type
- the term includes but is not limited to autoantigens and fragments thereof involved in autoimmune attack.
- the term includes antigens normally not exposed to the immune system which become exposed in the locus of autoimmune attack as a result of autoimmune tissue destruction.
- antigens normally not exposed to the immune system which become exposed in the locus of autoimmune attack as a result of autoimmune tissue destruction.
- heatshock proteins although not specific to a particular tissue, are normally shielded from contact with the immune system.
- “Bystander suppression” is suppression at the locus of autoimmune attack of cells that contribute to autoimmune destruction; this suppression is mediated by the release of one or more immunosuppressive factors (including Th2-enhancing cytokines and Thl-inhibiting cytokines) from suppressor T-cells elicited by the ingestion (or inhalation) of a bystander antigen and recruited to the site where cells contributing to autoimmune destruction are found.
- the resulting downregulation by the secreted cytokines is antigen-nonspecific but locally restricted to the autoimmune responses responsible for tissue destruction.
- autoimmune non limiting examples are psoriasis, vitiligo, pemphigus vulgaris, dermatomyositis, alopecia areata, alopecia totalis, and alopecia universalis. Krueger, J., Nature Medicine 1(5) : 442 - 441 , May 1995; Wong, R.I. et al., Jmmunol. Today, 14 (2 ) :69-74, February 1993; Trentham, D.E. et al., Arthritis .Rheum, 24(11) :1363-9, November 1981; Goudie, R.B.
- Non limiting examples include atopic dermatitis, and contact dermatitis.
- the common characteristic of these diseases is that the antigen (whether endogenous or exogenous) is present in the microenvironment of the skin. Inflammation is caused by activated T-cells that recognize the antigen and aggregate at the locus of the antigen.
- T-cell mediated inflammatory skin disorders afflict a large number of people. For example, at least 1% of the United States population suffers from psoriasis. These diseases can be not only physically debilitating but also psychologically damaging (as can be the case, for example with both psoriasis and, especially for dark-skinned people, vitiligo) and often interfere with the victim's productivity, especially when the disease is occupationally related (as is often the case for example, with contact dermatitis) . Thus these diseases add considerably to the economic burden. There are no known cures for these T-cell mediated inflammatory skin disorders.
- Treatments currently in use are palliative and are accompanied by side-effects that are often at least as serious as the disease they are intended to treat.
- treatments for psoriasis include ultraviolet B(UVB) radiation, PUVA which involves topical or systemic administration of psoralens (P) combined with ultraviolet A (UVA) radiation, methotrexate administration, topical or systemic use of retinoids, and administration of global immunosuppressants, such as cyclosporin A.
- Vitiligo is also treated with PUVA or (less effectively) with topical steroids. Bleaching of the skin is also used but it is only effective in masking the depigmentation.
- dermatitis and localized alopecia areata are normally treated with topical steroids.
- Widespread alopecia areata is treated with cyclosporin A or steroids, systemically administered.
- PUVA therapy substantially increases the risk of skin carcinomas (sguamous cell carcinoma, malignant melanoma) and also causes premature (photo)aging.
- UVB therapy also has the same disadvantages although both the increase in the risk of malignancies and the photoaging damage are somewhat less pronounced.
- Methotrexate (used only for severe psoriasis cases) was developed as a chemotherapeutic drug and its administration has the usual side-effects of chemotherapy, including bone marrow suppression, immune suppression, and liver cirrhosis.
- Retinoids are teratogenic and cannot be administered to pregnant women. Moreover, a substantial number of patients have adverse reactions. Some of the most common serious side- effects of retinoids are: increase in blood triglycerides (which is thought to increase the risk of vascular and heart disease) , impaired liver function and benign intracranial hypertension.
- the present invention relates to methods for treating a mammalian (including a human) skin disorder presenting with T-cell mediated (or T-cell dependent) inflammation comprising administering to a mammal in need of treatment via the oral route a "skin-associated bystander antigen" (defined below) in an amount effective to suppress said inflammation.
- the present invention relates to methods of suppressing T-cell mediated or T-cell dependent inflammation of the skin associated with a skin disorder comprising administering to a mammal in need of treatment a skin-associated bystander antigen in an amount effective to suppress said inflammation.
- the invention relates to compositions and dosage forms that: contain at least one skin- associated bystander antigen; are adapted for oral administration; and are useful in the foregoing methods.
- Fig. 1 is a plot of the change in footpad thickness (expressed in mm compared to unchallenged controls) for each of three experimental groups of mice: G3 fed Factor XIII (a skin-specific bystander antigen) ; G2 fed hen egg lysozyme (HEL) ; and Gl fed PBS (positive control group) ; immunized in the right flank with Factor XIII and in the left flank with HEL; and then challenged with HEL.
- Factor XIII a skin-specific bystander antigen
- HEL hen egg lysozyme
- PBS positive control group
- T-cell mediated inflammation is induced by a first (sensitizing) immunization followed by challenge with the same antigen as that used to sensitize the experimental animal.
- Challenge is usually administered in either the ear or the footpad of the animal, where there is a relative abundance of skin (as opposed to other tissue) and thus inflammation of the skin is induced.
- the DTH system has been extensively used as a template for assessing the effect of various methods and substances on T- cell mediated inflammation. Ferguson, T.A. et al., PNAS (USA) 88:8072-8076, 1991, Ohmen, J.D. et al. J". Immunol .
- the DTH system effectively emulates the presence of an antigen (endogenous or exogenous) in skin and elicits activated T-cells that are reactive with this antigen.
- bystander suppression causes regulatory (suppressor) T-cells to be induced in the gut-associated lymphoid tissue (GALT) or, in the case of by-inhalation administration, mucosa associated lymphoid tissue (MALT) .
- GALT gut-associated lymphoid tissue
- MALT mucosa associated lymphoid tissue
- T-cells elicited by the bystander antigen are targeted to the locus of autoimmune attack where they mediate the local release of certain immunoregulatory factors and cytokines, such as transforming growth factor beta (TGF-0) , interleukin-4 (IL-4) or interleukin-10 (IL-10) .
- TGF-0 transforming growth factor beta
- IL-4 interleukin-4
- IL-10 interleukin-10
- IL-4 and IL-10 are also antigen-nonspecific immunoregulatory cytokines.
- IL-4 in particular enhances Th2 response, i.e. acts on T-cell precursors and causes them to differentiate preferentially into Th2 cells.
- IL-4 also indirectly inhibits Thl exacerbation.
- IL-10 is a direct inhibitor of Thl responses.
- a skin-associated bystander antigen is effective to suppress (i.e., eliminate or diminish) a T-cell mediated inflammatory immune response associated with T-cell mediated inflammatory skin disorders.
- Skin-associatedbystander antigens that canbe used for this purpose are defined herein to include any skin- associated antigen exposed to the immune system (either normally or as a result of the inflammatory process) that can be recognized by T-cells of the recipient mammal (as assessed for example by proliferation assay) .
- the definition of "bystander antigens" in the prior applications referenced above is thus also valid here with the additional requirement that the bystander antigen be "skin associated", i . e.
- the skin-associated bystander antigen must come into contact with the immune system either normally, i.e., in the absence of inflammation, or must become exposed to the immune system as a result of inflammation.
- fragments of the naturally occurring skin-associated bystander antigens that contain at least one epitope which would be recognized (in the context of antigen presentation) by the T- cells of a subject to be treated. The fragment thus can be a ligand to a T-cell receptor, or even an epitope that is recognized by autoreactive T-cells.
- the bystander antigen need not be the primary or a primary target of the T-cells causing the inflammation. For example, even if the skin-disorder is autoimmune in nature, the bystander antigen need not be an autoantigen.
- Non limiting examples of skin-associated bystander antigens that can be used to treat any skin disorder presenting with inflammation include Type I, Type III or Type IV collagen; basal keratins (such as K5 or K14) and superbasal keratins
- transglutaminases such as transglutaminase 1 and transglutaminase 5 (a/k/a Factor XIII) .
- melanocyte-specific enzyme tyrosinase is useful specifically in treatment of vitiligo
- Keratin K16 (specific to hair follicles) is useful specifically in treatment of alopecia areata, totalis, or universalis
- antigen Jo-1 as well as other aminoacyl t-RNA synthetases (Plotz et al. in Manual of Biological Markers of Disease, B6.1:1-118, 1994) useful specifically in the treatment of myositis.
- human-derived skin-associated bystander antigens either expressed by recombinant techniques or purified from natural sources.
- Impure constructs or preparations containing one (or more) such antigens can be employed.
- a nonlimiting example of a class of constructs are synthetic chimeric peptides and polypeptides containing one or more T-cell epitopes of ligands of a skin-associated bystander antigen.
- the ability to suppress inflammation with oral administration of impure preparations containing mixtures of skin-associated bystander antigens has been seen in experiments by the present inventors using whole keratinocytes as the fed antigen (data not shown) .
- corresponding skin-associated antigens of mammalian origin e.g. chicken and bovine collagens, porcine keratin, turkey keratin
- guinea pig transglutaminase are commercially available (e.g. from Sigma Chemical Co., St. Louis, Mo.) or have known nucleotide and/or amino acid sequences. If animal-derived skin-associated bystander antigens are used in treating humans, it is preferred to use those animal-derived antigens that are the most closely homologous to the corresponding human antigens.
- Effective amounts of the skin-associated bystander antigens are generally within the range of 0.1 mg-100 mg per treatment (dose) per mammalian subject (including a human) . The exact amount may vary with the subject and it may also vary according to the ability of the subject's T-cells to recognize the antigen (e.g., it will be necessary to administer higher amounts of a weak antigen) . Effectiveness in inducing suppression is dose-dependent and there is an optimum effective dose, which is best ascertained by routine experimentation. For collagen I and IV a useful dosage range is 0.1-10 mg/ patient/treatment, preferably 0.1-5 mg. For Factor XIII, an effective dose range for humans is also 0.1-10 mg, preferably 1-10 mg.
- an effective dose range in humans is 0.1-10 mg. Effectiveness of treatment (suppression of inflammation) can be assessed by physical examination of the afflicted area and reduction or disappearance of skin lesions, depigmentation, or inhibition of hair loss, depending on the disease being treated, as further discussed below.
- the frequency of treatment (for mammals including humans) can vary, e.g. daily, every other day, once or twice a week, once a month. It is also possible to administer multiple daily doses. At the commencement of treatment it is preferred to administer the skin-associated bystander antigen more frequently (e.g. every day or every other day) and the frequency can be tapered (to e.g. once a week or once a month) as treatment progresses.
- Determination of the optimum frequency of administration is within the skill of the art in light of the present description and will vary with the patient's age and physical condition as well as with the severity of the disorder. It is best determined on an individual basis by the attending physician, using the information given herein and the skill of the art.
- the duration of treatment can vary from several days (e.g. ten) to several weeks (e.g. four) to several months (e.g. six) to indefinitely.
- treatment is expected to last preferably at least three months and can be continued as long as benefits persist because of the low toxicity of the treatment.
- the skin-associated bystander antigens employed in the present invention can be administered in various solid or liquid formulations suitable for oral consumption.
- Each oral formulation containing skin-associated bystander antigen according to the present invention may additionally comprise inert constituents including pharmaceutically acceptable carriers, diluents, fillers, solubilizing or emulsifying agents, and salts, as is well-known in the art.
- tablets may be formulated in accordance with conventional procedures employing solid carriers well-known in the art.
- Capsules employed in the present invention may be made from any pharmaceutically acceptable material, such as gelatin, or cellulose derivatives.
- Sustained release oral delivery systems and/or enteric coatings for orally administered dosage forms are also contemplated, such as those described in U.S. Patent No. 4,704,295, issued November 3, 1987; U.S. Patent No.
- solid carriers include starch, sugar, bentonite, silica, and other commonly used carriers.
- carriers and diluents which may be used in the formulations of the present invention include saline, syrup, dextrose, and water.
- Liquid formulations are preferably solutions; if the skin-associated bystander is insoluble in water, it can be solubilized and/or the pH can be adjusted as is well known in the art; or the antigen can be partially -hydrolyzed or administered as a suspension. It will be appreciated that the unit content of active ingredient or ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount, since the necessary effective amount can be reached by administration of a plurality of dosage units (such as capsules or tablets or combinations thereof) .
- the bystander antigens of the present invention may be administered in single dosage form or in multiple dosage forms.
- dosages for mammals and human dosages can be determined by beginning with a relatively low dose of skin-associated bystander antigen, progressively increasing it (e.g. logarithmically) and measuring a biological reaction to the treatment, for example induction of regulatory cells (CD4 + and/or CD8 + ) as described in Chen, Y. et al., Science, 1994, supra, reduction in class II surface markers on circulating T-cells, and/or by assessing the disease severity, according to well-known methods.
- regulatory cells CD4 + and/or CD8 +
- Psoriasis Size and extent plaques and associated salmon-pink erythema and silvery scale; papules, pustules and nail deformity.
- Vitiligo Surface area (size) and coloration of depigmented macules or patches, hypopigmented lesions, trichrome macules or patches; inflamed borders of depigmented areas, irritation or rash (which often precedes pigment loss) .
- Contact dermatitis Standardized patch test used in diagnosis performed according to procedures prescribed by the supplier, skin biopsy, open application of suspected or known causative agent, and prick or scratch skin test; appearance of redness, blisters, cracks, scales, welts, dryness or rash; burning itching or stinging sensation (reported by the patient) , improvement measured by reduction in skin reaction or in skin lesions.
- Alopecia Areata Burning, itching, tingling before hair loss or concurrent with hair growth; location, number and surface area of lesions; microscopic examination of hair; biopsy.
- Atopic Dermatitis Extent and severity of lesion characteristics such as excoriation, xerosis, ichthyosis, palmar hyperlinearily, keratosispilaris, erythema, periorbital darkening, pityriasis, alba.
- the optimum dosage will be the one having the greatest influence on the biological phenomenon being measured, such as that which causes the greatest decrease in disease symptoms.
- An effective dosage range will be one that causes at least a statistically or clinically significant attenuation of at least one symptom characteristic of the disease being treated, or a significant change of a marker (such as the frequency of regulatory or activated T-cells) .
- Administration of skin-associated bystander antigens can be conjoined to preferably oral administration of one or more enhancers, i.e. substances that enhance the tolerizing effect of the skin-associated bystander antigen, such as LPS, Lipid A (as described in U.S. Application Serial No. 08/202,677) IL-4, IL-10 or Type I interferon (See, e.g. U.S. Application Serial No. 08/420,980 and 08/420,979) .
- enhancers i.e. substances that enhance the tolerizing effect of the skin-associated bystander antigen, such as LPS, Lipid A (as described in U.S. Application Serial No. 08/202,677) IL-4, IL-10 or Type I interferon (See, e.g. U.S. Application Serial No. 08/420,980 and 08/420,979) .
- enhancers i.e. substances that enhance the tolerizing effect of the skin-associated bystander antigen,
- oral administration includes oral, enteral or intragastric administration; i.e., it includes any administration that brings the skin-associated bystander antigen in contact with gut-associated lymphoid tissue (GALT) .
- GALT gut-associated lymphoid tissue
- an alternative method of achieving tolerance in the present invention is by administration (called mucosal administration and including inhalation, buccal and nasal administration) by which the skin- associated bystander antigen is placed in contact with the buccal, nasal, bronchial or pulmonary mucosa.
- mucosal administration and including inhalation, buccal and nasal administration
- the amounts of antigen that will be effective in mucosal administration are expected to be somewhat lower than those used in oral administration, i.e., within the lower half of the ranges and preferably within the lower third of the ranges given above.
- Formulations useful for mucosal administration include those suitable for administration of polypeptides across the mucosal membrane.
- U.S. Patent Nos. 4,226,848 and 4,690,683 describe polymeric matrices useful in administering pharmaceuticals into the nasal cavity.
- U.S. Patent No. 4.952,560 discloses an ointment formulation comprising a water-soluble protein and a monohydric alcohol which may be suitable for use in administering the present invention because it increases absorption of drugs across epithelial barriers. Methods of improving transcutaneous absorption of materials is described in U.S. Patent No. 4,272,516. Each of these formulations and others well known in the art may be used for mucosal delivery of bystander antigen as described in the present invention.
- Additional suitableformulations includecommercially available vehicles and formulations which may but need not include surface active agents and other skin penetrants as absorption promoters.
- U.S. Patent No.5,407, 911 describes the use of axacycloalkane derivatives as absorption promoters for high molecular weight polypeptides.
- U.S. Patent No. 5,397,771 describes the use of n-glycofurols in methods of administering pharmaceutical compositions across the mucosal membrane.
- U.S. Patent No. 4,548,922 discloses the use of water-soluble amphophilic steroids to increase absorption.
- Gel-based compositions such as those described in Morimoto et al. (Chem. Pharm. Bull .
- 35(7) :3041-3044) are also suitable for the present invention.
- the purpose of mucosal administration of bystander antigens of the present invention is to place them into contact with the immune system at the mucosa associated lymphoid tissue and not to deliver these substances in the bloodstream. Accordingly, the absorption promoters of the foregoing formulations may be decreased or eliminated. Determination of what parameters should be altered is well within the skill of the art.
- Formulations administered by inhalation in aerosol form are also contemplated for use with the present invention.
- General guidance as to formulation of aerosol dosages is given in Barr, Prac. Pharm. 19(11) :675-678.
- U.S. Patent No. 4,352,789 describes an aerosol formulation for the administration of finely divided solid materials which can be used with the present invention.
- U.S. Patent No. 3,739,951 discloses a method of administering a liquid formulation in an aerosol form. Aerosol delivery of bystander antigens is described in co-pending, commonly assigned U.S. Application 08/419,502.
- the skin-associated bystander antigen be administered as a solution rather than a suspension.
- the antigens may first be solubilized or hydrolyzed, or fragments of the naturally occurring antigens can be used.
- the inhalable pharmaceutical formulations of the present invention may be administered in the form of an aerosol spray using, for example, a nebulizer such as those described in U.S. Patent Nos. 4,624,251 issued November 25, 1986; 3,703,173 issued November 21, 1972; 3,561,444 issued February 9, 1971 and 4,635,627 issued January 13, 1971; 4,548,922 issued Oct. 22, 1985 (it should be noted that use of absorption promoters is not necessary in the practice of the present invention) .
- the aerosol material is inhaled by the subject to be treated. In the present examples (and for purposes of accuracy) the animals treated with aerosol agents were retained in enclosed (airtight) cages, into which the aerosol was dispensed. Thus, the amount of material per unit of area could be determined and the results quantified in terms of unit of aerosol material per unit volume of cage area.
- Aerosol delivery systems of the type disclosed herein are available from numerous commercial sources including Fisons Corporation (Bedford, MA) , Schering Corp. (Kenilworth, NJ) and American Pharmoseal Co., (Valencia, CA) . All documents cited herein are incorporated by reference in their entirety. In case of conflicts, the present specification including its definitions controls.
- PBS antigens
- T-cell Stimulation Mice fed and immunized as described in the preceding paragraph were sacrificed 14 days after immunization and their inguinal lymph nodes excised; T- cells were stimulated with antigen in vitro for 72 hours and then pulsed with 1 ⁇ Ci tritiated thymidine per 5 x 10 3 cells and incubated for 16 hours. The cells were then harvested and thymidine uptake was assessed as counts per minute relative to unstimulated controls.
- Cvtokine Production Primary T-cell cultures were stimulated with antigen; supernatants were removed after 40 or 72 hours and assayed by ELISA for IL-4, IL-10, IL-2 and IFN- ⁇ (40-hour supernatant) and TGF-0 (72-hour supernatant) using appropriate antibodies commercially available from Pharmingen, San Diego, CA (for IL-2, IL-4, IL-10 and IFN- ⁇ ); and from Celtrix Pharmaceuticals, Santa Clara, CA and R&D, Minneapolis, MN (for TGF-/8) .
- EXAMPLE 1 Delayed-Type Hypersensitivity Response is Suppressed by Feeding Skin-Associated Bystander
- mice Three groups of mice were fed as follows: Group 1: phosphate-buffered saline (PBS); Group 2: 3O ⁇ g/mouse/feeding of hen-egg lysozyme (HEL; used as the nonskin-associated antigen); Group 3: 30 ⁇ g/mouse/feeding of transglutaminase 5 (Factor XIII from Zymogenetics, Palo Alto, CA) according to the aforedescribed schedule. All groups were immunized with 100 ⁇ g Factor XIII in CFA in the right flank and with 100 ⁇ g HEL in the left flank, and subsequently challenged with the 50 ⁇ g of the same antigen in the corresponding footpad. The results ( ⁇ thickness, in mm) are set forth in Fig. 1 for the left footpad.
- Group 1 PBS-fed
- Group 2 HEL-fed
- Group 3 was the experimental group because it was fed a skin-associated bystander antigen which was intended to suppress inflammation
- HEL hyposensitivity induced by another antigen (HEL) which was only associated with skin artificially (i.e., in the experimental milieu because it was injected subcutaneously) and does not normally occur in skin.
- Fig. 1 show that feeding Factor XIII suppressed inflammation induced with HEL as much as feeding HEL.
- feeding a skin-associated bystander antigen i.e. an antigen concentrated in the afflicted tissue but not causally involved in the inflammatory process, causes suppression. This constitutes proof of principle of the operability of the present invention.
- mice were fed 3, 30 or 300 ⁇ g or 1 mg of Factor XIII and immunized and challenged with HEL, as described in Example 1.
- the dosage of 30 ⁇ g Factor XIII produced the strongest suppression, and is a preferred dosage for this antigen and these mammals (data not shown) .
- IL-2 0 pg/ml 22 pg/ml
- TGF-0 3780 pg/ml 1225 pg/ml
- IL-10 7435 pg/ml 0
- Example A Three patients diagnosed with psoriasis and receiving no other treatment will be administered orally 5 mg of Factor XIII (Patient Al) ; 1 mg of Collagen I (Patient A2) , or 5 mg of Keratin 5 (Patient A3) .
- the skin-associated bystander antigen will be preferably administered in aqueous suspension or solution.
- Collagen I can be solubilized by known methods and dissolved in 0.1 M acetic acid.
- Factor XIII (which may be lyophilized as is well-known) is soluble in water.
- Keratin 5 is insoluble in water but may be micronized according to known methods and administered in an aqueous suspension, or may be partially hydrolyzed.
- the frequency of administration will be daily for one month and then depending on the patient's response to the treatment may be continued or its frequency may be progressively reduced to once weekly and then once monthly for the duration of the treatment (anticipated to last 3 months or longer) .
- Assessment of effectiveness will be made by physical examination. It is anticipated that each patient will experience a substantial decrease in skin symptom(s) .
- Example B Three patients diagnosed with atopic dermatitis and receiving no other treatment will be administered orally 5 mg of Factor XIII (Patient Bl) ; 1 mg of Collagen I (Patient B2) , or 5 mg of Keratin 5 (Patient B3) formulated as in example A.
- the frequency of administration will be daily for one month and then reduced to once weekly for at least one more month. Assessment of effectiveness will be made by physical examination. It is anticipated that each patient will experience significant decrease in the number and severity of lesions.
- Example C Three patients diagnosed with vitiligo and receiving no other treatment will be administered orally 5 mg of Factor XIII (Patient Cl) ; 1 mg of Collagen I (Patient C2) , or 5 mg of Keratin 5 (Patient C3) formulated as in Example A.
- the frequency of administration will be daily for 1-3 months and then reduced to twice weekly for 1-3 months followed by administration once a month for the remainder of therapy.
- Assessment of effectiveness will be made by physical examination. It is anticipated that each patient will experience a measurable decrease in the area and/or intensity of depigmentation, and or other vitiligo-associated symptoms detailed supr .
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Mycology (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Marine Sciences & Fisheries (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96922475A EP0871478A1 (en) | 1995-06-07 | 1996-06-05 | Oral tolerance in skin diseases presenting with t-cell mediated inflammation |
BR9609014-6A BR9609014A (en) | 1995-06-07 | 1996-06-05 | Medicines to treat a mammal suffering from an epithelial disorder and to treat a mammal suffering from median t-cell or t-cell-dependent inflammation of a mammal's skin |
AU63337/96A AU6333796A (en) | 1995-06-07 | 1996-06-05 | Oral tolerance in skin diseases presenting with t-cell media ted inflammation |
JP9502280A JPH11507383A (en) | 1995-06-07 | 1996-06-05 | Oral tolerance in skin diseases manifested with T-cell mediated inflammation |
NO975554A NO975554L (en) | 1995-06-07 | 1997-12-02 | Oral tolerance in skin diseases present with T-cell mediated inflammation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US48619095A | 1995-06-07 | 1995-06-07 | |
US486,190 | 1995-06-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996040232A1 true WO1996040232A1 (en) | 1996-12-19 |
Family
ID=23930947
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/010384 WO1996040232A1 (en) | 1995-06-07 | 1996-06-05 | Oral tolerance in skin diseases presenting with t-cell mediated inflammation |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0871478A1 (en) |
JP (1) | JPH11507383A (en) |
KR (1) | KR19990022556A (en) |
AU (1) | AU6333796A (en) |
BR (1) | BR9609014A (en) |
CA (1) | CA2219457A1 (en) |
HU (1) | HUP9901077A3 (en) |
IL (1) | IL122502A0 (en) |
NO (1) | NO975554L (en) |
WO (1) | WO1996040232A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999064066A1 (en) * | 1998-06-09 | 1999-12-16 | Shionogi & Co., Ltd. | Immune tolerance-inducing agents containing hard keratin or keratin-like substance |
JP4834219B2 (en) * | 1998-10-04 | 2011-12-14 | ヴァスキュラー バイオジェニックス リミテッド | Composition for prevention and / or treatment of atherosclerosis |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102027451B1 (en) | 2012-11-02 | 2019-10-02 | (주)아모레퍼시픽 | Micro RNA, and screening method using the micro RNA |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5399347A (en) * | 1987-06-24 | 1995-03-21 | Autoimmune, Inc. | Method of treating rheumatoid arthritis with type II collagen |
-
1996
- 1996-06-05 KR KR1019970709037A patent/KR19990022556A/en not_active Application Discontinuation
- 1996-06-05 AU AU63337/96A patent/AU6333796A/en not_active Abandoned
- 1996-06-05 HU HU9901077A patent/HUP9901077A3/en unknown
- 1996-06-05 EP EP96922475A patent/EP0871478A1/en not_active Withdrawn
- 1996-06-05 CA CA002219457A patent/CA2219457A1/en not_active Abandoned
- 1996-06-05 WO PCT/US1996/010384 patent/WO1996040232A1/en not_active Application Discontinuation
- 1996-06-05 JP JP9502280A patent/JPH11507383A/en active Pending
- 1996-06-05 BR BR9609014-6A patent/BR9609014A/en unknown
- 1996-06-05 IL IL12250296A patent/IL122502A0/en unknown
-
1997
- 1997-12-02 NO NO975554A patent/NO975554L/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5399347A (en) * | 1987-06-24 | 1995-03-21 | Autoimmune, Inc. | Method of treating rheumatoid arthritis with type II collagen |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999064066A1 (en) * | 1998-06-09 | 1999-12-16 | Shionogi & Co., Ltd. | Immune tolerance-inducing agents containing hard keratin or keratin-like substance |
JP4834219B2 (en) * | 1998-10-04 | 2011-12-14 | ヴァスキュラー バイオジェニックス リミテッド | Composition for prevention and / or treatment of atherosclerosis |
Also Published As
Publication number | Publication date |
---|---|
BR9609014A (en) | 1999-12-14 |
HUP9901077A3 (en) | 1999-11-29 |
JPH11507383A (en) | 1999-06-29 |
HUP9901077A2 (en) | 1999-07-28 |
KR19990022556A (en) | 1999-03-25 |
AU6333796A (en) | 1996-12-30 |
NO975554D0 (en) | 1997-12-02 |
NO975554L (en) | 1997-12-02 |
IL122502A0 (en) | 1998-06-15 |
CA2219457A1 (en) | 1996-12-19 |
EP0871478A1 (en) | 1998-10-21 |
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