Methods of inducing indolamine 2,3 - dioxygenase (ido)

Abstract

A composition and method for using a composition, the composition having at least two compounds, each of which induces indolamine 2,3-dioxygenase, for the treatment of an autoimmune disorder or disease or immune rejection of transplants or gene therapeutically modified cells, wherein the inducers have different mechanism of action and wherein the composition gives rise to a synergistic effect on the IDO levels.

1 . A composition comprising at least two compounds each of which induces indolamine 2,3-dioxygenase (IDO) wherein the at least two compounds induce IDO by different mechanisms of action, wherein the composition gives rise to a synergistic effect on the IDO level compared to the sum of the IDO level achieved with each of the at least two compounds when used alone, wherein one of the at least two compounds is zebularine and another one of the at least two compounds is selected from the list consisting of interferon gamma, interferon A and human chorionic gonadotropine. 
     
     
         2 . The composition according to  claim 1 , wherein the composition comprises: zebularine and interferon gamma. 
     
     
         3 . The composition according to  claim 2 , wherein the composition comprises:
 (i) zebularine, interferon gamma and interferon A;   (ii) zebularine, interferon gamma and valproic acid;   (iii) zebularine, interferon gamma and TGF-beta; or   (iv) zebularine, interferon gamma, interferon A and TGF-beta.   
     
     
         4 . The composition according to  claim 1 , wherein the composition comprises: zebularine and interferon A. 
     
     
         5 . The composition according to  claim 1 , wherein the composition comprises: zebularine and human chorionic gonadotropine. 
     
     
         6 . The composition according to  claim 1 , wherein said composition further comprises a pharmaceutically acceptable buffer, excipient, diluent, solvent or carrier. 
     
     
         7 . A cell culture comprising:
 IDO-inducible cells in which IDO has been induced; and   a suitable medium,   the cell culture comprising a composition comprising at least two compounds each of which induces indolamine 2,3-dioxygenase (IDO), wherein the at least two compounds induce IDO by different mechanisms of action, wherein the composition gives rise to a synergistic effect on the IDO level compared to the sum of the IDO level achieved with each of the at least two compounds when used alone, wherein one of the at least two compounds is zebularine and another one of the at least two compounds is selected from the list consisting of interferon gamma, interferon A and human chorionic gonadotropine, and isolated cells in a medium.   
     
     
         8 . The cell culture according to  claim 7 , wherein the IDO-inducible cells are dendritic cells or antigen presenting cells. 
     
     
         9 . The cell culture according to  claim 7 , wherein the IDO-inducible cells are monocytic cells. 
     
     
         10 . The cell culture according to  claim 7 , wherein the medium is RPMI medium. 
     
     
         11 . The cell culture according to  claim 7 , wherein the composition comprises: zebularine and interferon gamma. 
     
     
         12 . The cell culture according to  claim 8 , wherein the composition comprises:
 (i) zebularine, interferon gamma and interferon A;   (ii) zebularine, interferon gamma and valproic acid;   (iii) zebularine, interferon gamma and TGF-beta; or   (iv) zebularine, interferon gamma, interferon A and TGF-beta.   
     
     
         13 . The cell culture according to  claim 7 , wherein the composition comprises: zebularine and interferon A. 
     
     
         14 . The cell culture according to  claim 7 , wherein the composition comprises: zebularine and human chorionic gonadotropine. 
     
     
         15 . A method of treating a mammal having an autoimmune disorder or disease or suffering from immune rejection of organs, tissues, normal cells or gene therapeutically modified cells, wherein the treatment induces IDO, comprising firstly a treatment ex vivo of cells derived from the treated mammal or from another mammal, with a therapeutically effective amount of the composition according to  claim 1  and in the presence of one or more antigens associated with a condition being treated, followed by the transfer of treated cells to the mammal being treated. 
     
     
         16 . The method according to  claim 15 , which is a method of treating a disease selected from the group consisting of Achlorhydria, Acute hemorrhagic leukoencephalitis, Addison's Disease, Alopecia Areata, Pernicious Anemia, Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome, Aplastic Anemia, Atopic Allergy, Autoimmune Atrophic Gastritis, Autoimmune Hearing Loss, Autoimmune hemolytic anemia, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune Lymphoproliferative Syndrome, Autoimmune Myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy, Polyglandular Autoimmune Syndrome Type II, Behcet Syndrome, Celiac Disease, Chagas Disease, Sclerosing Cholangitis, Chronic Inflammatory Demyelinating Polyneuropathy, Chronic lymphocytic thyroiditis, Churg-Strauss Syndrome, Ulcerative Colitis, Crohn's disease, Cryoglobulinemia, Cushing's Syndrome, Dermatitis Herpetiformis, Dermatomyositis, Diabetes Mellitus (Insulin-Dependent), Diffuse Cerebral Sclerosis of Schilder, Epidermolysis Bullosa Acquisita, Felty's Syndrome, Membranous Glomerulonephritis, Goodpasture Syndrome, Graves' Disease, Guillain-Barre Syndrome, Hamman-Rich Syndrome, Autoimmune Hepatitis, Chronic Active Hepatitis, Inflammatory Bowel Diseases, Lambert-Eaton Myasthenic Syndrome, Lens-induced uveitis, Lichen Sclerosus et Atrophicus, Discoid Lupus Erythematosus, Systemic Lupus Erythematosus, Lupus Hepatitis, Lupus Nephritis, Lymphopenia, Meniere's Disease, Mixed Connective Tissue Disease, Mooren's ulcer, Mucocutaneous Lymph Node Syndrome, Multiple Sclerosis, Myasthenia Gravis, Transverse Myelitis, Myocarditis, Narcolepsy, Neuromyelitis Optica, Oculovestibuloauditory Syndrome, Sympathetic Ophthalmia, Opsoclonus-Myoclonus Syndrome, Pancreatitis, Bullous Pemphigoid, Pemphigus foliaceus, Pemphigus Vulgaris, Polyarteritis Nodosa, Relapsing Polychondritis, Autoimmune Polyendocrinopathy, Polymyalgia Rheumatica, Polyradiculoneuropathy, Primary biliary cirrhosis, Psoriasis, Idiopathic Thrombocytopenic Purpura, Raynaud's Disease, Reiter's Disease, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Ankylosing Spondylitis, Stiff-Person Syndrome, Adult-Onset Still's Disease, Takayasu Arteritis, Temporal Arteritis, Thyrotoxicosis, Type B Insulin Resistance, Uveomeningo-encephalitic Syndrome, Wegener's Granulomatosis, and Vitiligo. 
     
     
         17 . The method according to  claim 15 , which is a method of treating a disease selected from the group consisting of Rheumatoid arthritis, Diabetes mellitus type I, Psoriasis, Sjogren's syndrome, Multiple Sclerosis, Crohn's disease, arteriosclerosis, Parkinson's disease, ALS (Amyotrophic lateral sclerosis) and dementia. 
     
     
         18 . The method according to  claim 15 , wherein one or more antigens are autoantigens responsible for an autoimmune disease. 
     
     
         19 . A method of treating a mammal having an autoimmune disorder or disease or having an immune rejection of transplants or gene therapeutically modified cells, wherein the treatment induces IDO, comprising administering to a patient a therapeutically effective amount of the composition according to  claim 1 . 
     
     
         20 . The method according to  claim 19 , which is a method of treating a disease selected from the group consisting of Achlorhydria, Acute hemorrhagic leukoencephalitis, Addison's Disease, Alopecia Areata, Pernicious Anemia, Anti-Glomerular Basement Membrane Disease, Antiphospholipid Syndrome, Aplastic Anemia, Atopic Allergy, Autoimmune Atrophic Gastritis, Autoimmune Hearing Loss, Autoimmune hemolytic anemia, Autoimmune hypoparathyroidism, Autoimmune hypophysitis, Autoimmune Lymphoproliferative Syndrome, Autoimmune Myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal-Dystrophy, Polyglandular Autoimmune Syndrome Type II, Behcet Syndrome, Celiac Disease, Chagas Disease, Sclerosing Cholangitis, Chronic Inflammatory Demyelinating Polyneuropathy, Chronic lymphocytic thyroiditis, Churg-Strauss Syndrome, Ulcerative Colitis, Crohn's disease, Cryoglobulinemia, Cushing's Syndrome, Dermatitis Herpetiformis, Dermatomyositis, Diabetes Mellitus (Insulin-Dependent), Diffuse Cerebral Sclerosis of Schilder, Epidermolysis Bullosa Acquisita, Felty's Syndrome, Membranous Glomerulonephritis, Goodpasture Syndrome, Graves' Disease, Guillain-Barre Syndrome, Hamman-Rich Syndrome, Autoimmune Hepatitis, Chronic Active Hepatitis, Inflammatory Bowel Diseases, Lambert-Eaton Myasthenic Syndrome, Lens-induced uveitis, Lichen Sclerosus et Atrophicus, Discoid Lupus Erythematosus, Systemic Lupus Erythematosus, Lupus Hepatitis, Lupus Nephritis, Lymphopenia, Meniere's Disease, Mixed Connective Tissue Disease, Mooren's ulcer, Mucocutaneous Lymph Node Syndrome, Multiple Sclerosis, Myasthenia Gravis, Transverse Myelitis, Myocarditis, Narcolepsy, Neuromyelitis Optica, Oculovestibuloauditory Syndrome, Sympathetic Ophthalmia, Opsoclonus-Myoclonus Syndrome, Pancreatitis, Bullous Pemphigoid, Pemphigus foliaceus, Pemphigus Vulgaris, Polyarteritis Nodosa, Relapsing Polychondritis, Autoimmune Polyendocrinopathy, Polymyalgia Rheumatica, Polyradiculoneuropathy, Primary biliary cirrhosis, Psoriasis, Idiopathic Thrombocytopenic Purpura, Raynaud's Disease, Reiter's Disease, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Ankylosing Spondylitis, Stiff-Person Syndrome, Adult-Onset Still's Disease, Takayasu Arteritis, Temporal Arteritis, Thyrotoxicosis, Type B Insulin Resistance, Uveomeningo-encephalitic Syndrome, Wegener's Granulomatosis, and Vitiligo.