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1. (WO2019046959) USE OF MIRTAZAPINE IN THE TREATMENT OF INFLAMMATORY DISORDERS, AUTOIMMUNE DISEASE AND PBC
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CLAIMS:

1 . A method of treating a subject having primary biliary cirrhosis, suspected of having primary biliary cirrhosis, or at risk of developing biliary cirrhosis, comprising: administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

2. The method of claim 1 , further comprising administering ursodeoxycholic acid (UDCA).

3. The method of claim 2, further comprising administering one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

4. The method of any one of claim 1 to 3, wherein the subject is a human.

5. A method of treating a subject having an inflammatory disorder, a subject suspected of having an inflammatory disorder, or a subject at risk of having an inflammatory disorder, comprising: administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

6. The method of claim 5, wherein the inflammatory disorder is one or more of chronic inflammation, acute inflammation, Celiac Disease, rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), asthma, encephalitis, chronic obstructive pulmonary disease (COPD), inflammatory osteolysis, Crohn's disease, ulcerative colitis, allergic disorders, septic shock, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), inflammatory vacultides (e.g. , polyarteritis nodosa, Wegner's granulomatosis, Takayasu's arteritis, temporal arteritis, and lymphomatoid granulomatosus), post-traumatic vascular angioplasty (e.g. restenosis after angioplasty), undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, chronic hepatitis, chronic inflammation resulting from chronic viral or bacterial infections, and acute inflammation, such as sepsis. In a particular embodiment, the immune-mediated inflammatory disease is selected from the group consisting of rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), or Crohn's disease.

7. The method of claim 5, further comprising administering ursodeoxycholic acid (UDCA).

8. The method of any one of claims 5 to 7, wherein the subject is a human.

9. A method of treating a subject having an autoimmune disease, a subject suspected of having an autoimmune disease, or a subject at risk of having autoimmune disease, comprising: administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

10. The method of claim 9, wherein the autoimmune disease is Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, autoimmune thyroiditis, autoimmune gastritis, autoimmune adrenalitis, autoimmune hypoparathyriodism, autoimmune diabetes, Crohn's disease, diabetes (Type I), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, paraneoplastic neurological disorders such as Lambert-Eaton Myasthenic Syndrome, inflammatory bowel disease, sarcoidosis, Achalasia, Adult Still's disease, Agammaglobulinemia, Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Amyloidosis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed

cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Hashimoto's thyroiditis, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, lgG4-related sclerosing disease, Inflammatory bowel disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Schmidt syndrome, Scleritis, Systemic sclerosis, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vogt-Koyanagi-Harada Disease or Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

1 1 . The method of claims 9, further comprising administering ursodeoxycholic acid (UDCA).

12. The method of any one of claims 9 to 1 1 , wherein said subject is a human.

13. A method of increasing the number of Treg cells in a subject, comprising: administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

14. A method of increasing the number of Breg cells in a subject, comprising: administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

15. The method of claim 13 or 14 wherein the subject is a human.

16. A method of treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Tregs, comprising administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

17. A method of treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Bregs, comprising administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

18. The method of claim 16 or 17, wherein disease, disorder, or condition, is an inflammatory disorder, or autoimmune disease, or PBC.

19. The method of claim 18, wherein the inflammatory disorder is chronic inflammation, acute inflammation, Celiac Disease, rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), asthma, encephalitis, chronic obstructive pulmonary disease (COPD), inflammatory osteolysis, Crohn's disease, ulcerative colitis, allergic disorders, septic shock, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), inflammatory vacultides (e.g. , polyarteritis nodosa, Wegner's granulomatosis, Takayasu's arteritis, temporal arteritis, and lymphomatoid granulomatosus), post-traumatic vascular angioplasty (e.g. restenosis after angioplasty), undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, chronic hepatitis, chronic inflammation resulting from chronic viral or bacterial infections, and acute inflammation, such as sepsis. In a particular embodiment, the immune-mediated inflammatory disease is selected from the group consisting of rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), or Crohn's disease.

20. The method of claim 18, wherein the autoimmune disease is Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, autoimmune thyroiditis, autoimmune gastritis, autoimmune adrenalitis, autoimmune hypoparathyriodism, autoimmune diabetes, Crohn's disease, diabetes (Type I), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, paraneoplastic neurological disorders such as Lambert-Eaton Myasthenic Syndrome, inflammatory bowel disease, sarcoidosis, Achalasia, Adult Still's disease, Agammaglobulinemia, Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Amyloidosis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Hashimoto's thyroiditis, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, lgG4-related sclerosing disease, Inflammatory bowel disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Schmidt syndrome, Scleritis, Systemic sclerosis, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vogt-Koyanagi-Harada Disease or Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

21 . The method of any one of claims 18, further comprising administering ursodeoxycholic acid (UDCA).

22. The method of any one of claims 16 to 21 , wherein said subject is a human.

23. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof, for treating a subject having primary biliary cirrhosis, suspected of having primary biliary cirrhosis, or at risk of developing biliary cirrhosis.

24. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof, in the manufacture of a medicament for treating a subject having primary biliary cirrhosis, suspected of having primary biliary cirrhosis, or at risk of developing biliary cirrhosis.

25. The use of claim 23 or 24, further comprising use of ursodeoxycholic acid (UDCA).

26. The use of claim 25, further comprising use of one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

27. The use of any one of claim 23 to 26, wherein the subject is a human.

28. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating a subject having an inflammatory disorder, a subject suspected of having an inflammatory disorder, or a subject at risk of having an inflammatory disorder.

29. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating a subject having an inflammatory disorder, a subject suspected of having an inflammatory disorder, or a subject at risk of having an inflammatory disorder.

30. The use of claim 28 or 29, wherein the inflammatory disorder is chronic inflammation, acute inflammation, Celiac Disease, rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), asthma, encephalitis, chronic obstructive pulmonary disease (COPD), inflammatory osteolysis, Crohn's disease, ulcerative colitis, allergic disorders, septic shock, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), inflammatory vacultides (e.g. , polyarteritis nodosa, Wegner's granulomatosis, Takayasu's arteritis, temporal arteritis, and lymphomatoid granulomatosus), post-traumatic vascular angioplasty (e.g. restenosis after angioplasty), undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, chronic hepatitis, chronic inflammation resulting from chronic viral or bacterial infections, and acute inflammation, such as sepsis. In a particular embodiment, the immune-mediated inflammatory disease is selected from the group consisting of rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), or Crohn's disease.

31 . The use of any one of claims 28 to 30, further comprising use of ursodeoxycholic acid (UDCA).

32. The use of any one of claims 28 to 31 , wherein the subject is a human.

33. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating a subject having an autoimmune disease, a subject suspected of having an autoimmune disease, or a subject at risk of having autoimmune disease.

34. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating a subject having an autoimmune disease, a subject suspected of having an autoimmune disease, or a subject at risk of having autoimmune disease.

35. The use of claim 33 or 34, wherein the autoimmune disease is Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, autoimmune thyroiditis, autoimmune gastritis, autoimmune adrenalitis, autoimmune hypoparathyriodism, autoimmune diabetes, Crohn's disease, diabetes (Type I), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, paraneoplastic neurological disorders such as Lambert-Eaton Myasthenic Syndrome, inflammatory bowel disease, sarcoidosis, Achalasia, Adult Still's disease, Agammaglobulinemia, Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Amyloidosis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Hashimoto's thyroiditis, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, lgG4-related sclerosing disease, Inflammatory bowel disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Schmidt syndrome, Scleritis, Systemic sclerosis, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vogt-Koyanagi-Harada Disease or Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

36. The use of any one of claims 33 to 34, further comprising use of ursodeoxycholic acid (UDCA).

37. The use of any one of claims 33 to 36, wherein said subject is a human.

38. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for increasing the number of Treg cells in a subject.

39. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for increasing the number of Treg cells in a subject.

40. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for increasing the number of Breg cells in a subject.

41 . Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for increasing the number of Breg cells in a subject.

42. The use of any one of claims 39 to 41 , wherein the subject is a human.

43. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Tregs.

44. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Tregs.

45. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Bregs.

46. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating a subject with a disease, disorder, or condition, that would benefit from an increase in the number of Bregs.

47. The use of any one of claims 43 to 46, wherein disease, disorder, or condition, is an inflammatory disorder, or autoimmune disease, or PBC.

48. The use of claim 47, wherein the inflammatory disorder is chronic inflammation, acute inflammation, Celiac Disease, rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), asthma, encephalitis, chronic obstructive pulmonary disease (COPD), inflammatory osteolysis, Crohn's disease, ulcerative colitis, allergic disorders, septic shock, pulmonary fibrosis (e.g. idiopathic pulmonary fibrosis), inflammatory vacultides (e.g. , polyarteritis nodosa, Wegner's granulomatosis, Takayasu's arteritis, temporal arteritis, and lymphomatoid granulomatosus), post-traumatic vascular angioplasty (e.g. restenosis after angioplasty), undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, chronic hepatitis, chronic inflammation resulting from chronic viral or bacterial infections, and acute inflammation, such as sepsis. In a particular embodiment, the immune-mediated inflammatory disease is selected from the group consisting of rheumatoid arthritis (RA), Inflammatory Bowel Disease (IBD), or Crohn's disease.

49. The method of claim 47, wherein the autoimmune disease is Addison's disease, alopecia areata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, autoimmune thyroiditis, autoimmune gastritis, autoimmune adrenalitis, autoimmune hypoparathyriodism, autoimmune diabetes, Crohn's disease, diabetes (Type I), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, paraneoplastic neurological disorders such as Lambert-Eaton Myasthenic Syndrome, inflammatory bowel disease, sarcoidosis, Achalasia, Adult Still's disease, Agammaglobulinemia, Achalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia, Amyloidosis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet's disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS) or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Hashimoto's thyroiditis, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammaglobulinemia, IgA Nephropathy, lgG4-related sclerosing disease, Inflammatory bowel disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere's disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Schmidt syndrome, Scleritis, Systemic sclerosis, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO), Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vogt-Koyanagi-Harada Disease or Wegener's granulomatosis (or Granulomatosis with Polyangiitis (GPA)).

50. The use of any one of claims 43 to 49, further comprising use of ursodeoxycholic acid (UDCA).

51 . The use of any one of claims 43 to 50, wherein said subject is a human.

52. A method for treating graft-versus-host disease (GVHD) in a subject, comprising administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

53. The method of claim 52, further comprising administering one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

54. The method of any one of claims 52 to 53, wherein said subject is a human.

55. A method of treating a subject to prevent or reduce rejection of transplantation of an organ in a subject, comprising administering a therapeutically effective amount of mirtazapine or a functional derivative thereof.

56. The method of claim 55, further comprising administering one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

57. The method of any one of claims 55 to 56, wherein said organ is a kidney, a liver, a heart, a lung, or a panceas.

58. The method of any one of claims 55 to 57, wherein said subject is a human.

59. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating graft-versus-host disease (GVHD) in a subject.

60. Use of a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating graft-versus-host disease (GVHD) in a subject.

61 . The use of claim 60, further comprising administering one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

62. The use of any one of claims 59 to 61 , wherein said subject is a human.

63. Use a therapeutically effective amount of mirtazapine or a functional derivative thereof for treating a subject to prevent or reduce rejection of transplantation of an organ in a subject.

64. Use of administering a therapeutically effective amount of mirtazapine or a functional derivative thereof in the manufacture of a medicament for treating a subject to prevent or reduce rejection of transplantation of an organ in a subject.

65. The use of claim 63 or 64, further comprising use of one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.

66. The use of any one of claims 63 to 65, wherein said organ is a kidney, a liver, a heart, a lung, or a pancreas.

67. The use of any one of claims 63 to 66, wherein said subject is a human.

68. A kit, comprising: mirtazapine or a functional derivative thereof, a container, and optionally instructions for the use thereof.

69. The kit of claim68, further comprising ursodeoxycholic acid (UDCA).

70. The kit of claim 68 or 69, further comprising one or more or obeticholic acid (INT-747), or other farnesoid X receptor agonists, NGM282, methotrexate, Fibrates (bezafibrate), Fibrates (Fenofibrate), MXB-8025, Budesonide, LUM001 (SHP625), Moexipril, Abatacept, Ustekinumab, rituximab, Mesenchymal Stem Cells, Truvada and Kaletra, Combivir (lamivudine and zidovudine), Pentoxifylline, or tetrathiomolybdate.