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Principal Investigator: John O'Shea
Organization: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Fiscal Year: 2023
Award: $268,550
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Cytokines comprise a large family of secreted proteins that regulate cell growth and differentiation of many types of cells. These factors are especially important in regulating immune and inflammatory responses, and regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of many autoimmune diseases such as rheumatoid arthritis, SLE, IBD and psoriasis, as well as viral cytokine storm dramatically revealed in COVID-19. Understanding the molecular basis of cytokine action provides important insights into the pathogenesis of immune-mediated disease and offers new therapeutic targets.
We discovered human Jak3, a kinase essential for signaling by cytokines that bind the common gamma chain, gc (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). We found that mutation of Jak3 results in a primary immunodeficiency disorder termed severe combined immunodeficiency (SCID). We have received two patents related to targeting Jak3 as the basis for a new class of immunomodulatory drugs and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate a series Jak antagonists. One compound, tofacitinib, was developed by Pfizer and found to be effective in preclinical models. Tofacitinib and other JAK inhibitors (jakinibs, including abrocitinib and ritlicitinib) are approved for rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, atopic dermatitis, vitiligo, alopecia areata, psoriasis, Crohn disease, ulcerative colitis and COVID-19.
Based on preclinical models, we considered that SLE might be an appropriate candidate for this class of drugs and performed a study in the NIH Clinical Center. We found that tofacitinib resulted in significant improvements in cardiometabolic and immunologic disease parameters associated with accelerated atherosclerosis in SLE, with response being associated with the presence of the STAT4 risk allele. Baricitinib has also been studied for dermatomyositis in the Clinical Center and other trials are being developed. This year we have identified patients with STAT4 and STAT6 gain-of-function variants who have been successfully treated with JAK inhibitors. We have also identified patients with SOCS1 loss of function mutations who are also being treated with JAK inhibitors. We have also developed a STAT1 GOF mouse and are using JAK inhibitors in this model to understand how to best utilize these drugs in the setting of interferonopathy.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acceleration><Allergic><Alopecia Areata><Arthritic Psoriasis><Arthritis><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Atrophic Arthritis><Autoimmune Diseases><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Bacteria><Binding><Binetrakin><Body Tissues><COVID-19><COVID-19 virus><COVID19><COVID19 virus><CRADA><CV-19><CV19><Cardiometabolic Disease><Cardiometabolic Disorder><Cell Differentiation><Cell Differentiation process><Cellular Expansion><Cellular Growth><Chronic Childhood Arthritis><Co-Stimulator><CoV-2><CoV2><Collaborations><Common Cytokine Receptor Gamma Chain><Common Cytokine Receptor γ Chain><Common Gamma Chain><Common γ Chain><Cooperative Research and Development Agreement><Costimulator><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cutaneous Disorder><Cytokine Signal Transduction><Cytokine Signaling><D12S1644><Dermatomyositis><Dermatopolymyositis><Dermatoses><Development><Disease><Disorder><Disseminated Neurodermatitis><Drug Utilization><Drugs><Epidermal Thymocyte Activating Factor><Family><Gamma Chain Interleukin 2 Receptor><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><Granulomatous Enteritis><Growth and Development><Growth and Development function><GvHD><HP40><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Homolog of Mouse T Cell and Mast Cell Growth Factor 40><Homologous Wasting Disease><Host Defense><Human><IL-15><IL-2><IL-4><IL-4-STAT><IL-7><IL-7 Gene><IL-9><IL15><IL15 Protein><IL2 Protein><IL21><IL4 Protein><IL7><IL7 Protein><IL7 gene><IL9 Protein><IMiD><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune modulatory therapeutic><Immune response><Immunes><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunodeficiency and Immunosuppression Disorders><Immunologic Deficiency Syndromes><Immunologic Diseases><Immunological Deficiency Syndromes><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inflammatory Muscle Diseases><Inflammatory Myopathy><Inflammatory Response><Interleukin 2><Interleukin 2 Precursor><Interleukin 2 Receptor Gamma><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin 9 Precursor><Interleukin II><Interleukin-15><Interleukin-15 Precursor><Interleukin-2><Interleukin-4><Interleukin-4 Precursor><Interleukin-7><Interleukin-7 Gene><Interleukin-9><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intermediary Metabolism><JAK kinase><Janus kinase><Juvenile Chronic Arthritis><Juvenile Chronic Polyarthritis><Juvenile Rheumatoid Arthritis><Kinases><Laboratories><Legal patent><Lupus Erythematosus Disseminatus><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><Lymphoid><Lymphopoietin-1><MCGF-2><MGC9721><Mast Cell Growth Factor-2><Mediating><Medication><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitogenic Factor><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutation><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Myositis><NIAMS><NIH><National Institute of Arthritis, and Musculoskeletal, and Skin Diseases><National Institutes of Health><Patents><Pathogenesis><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Polymyositis-Dermatomyositis><Pre-Clinical Model><Preclinical Models><Primary Immunodeficiency><Protein Secretion><Psoriasis><Psoriasis Arthropathica><Psoriatic Arthritis><Receptor Activation><Rheumatoid Arthritis><Risk-associated variant><Runt Disease><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SLE><STAT1><STAT1 gene><STAT4><STAT4 gene><STAT6><STAT6 gene><STAT6B><STAT6C><STAT91><Series><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe Combined Immunodeficiency><Severe Combined Immunodeficiency Syndrome><Severe Combined Immunologic Deficiency><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Skin Diseases><Skin Diseases and Manifestations><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T cell growth factor><T-Cell Growth Factor><T-Cell Growth Factor 2><T-Cell Growth Factor P40><T-Cell Stimulating Factor><T-Cell/Mast Cell Growth Factor p40><Testing><Thymocyte Stimulating Factor><Tissues><Transphosphorylases><Ulcerated Colitis><Ulcerative Colitis><United States National Institutes of Health><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><Vitiligo><Wuhan coronavirus><allergic dermatitis><allergic eczema><alopecia circumscripta><antagonism><antagonist><arthritic><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><autoimmune attack><autoimmune condition><autoimmune destruction><autoimmune disorder><autoimmune pathogenesis><autoimmunity disease><blood cell formation><cell growth><cell type><clinical center><combined T and B cell inborn immunodeficiency><congenital immunodeficiency><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><cutaneous disease><cytokine><cytokine release syndrome><cytokine storm><dermal disease><dermal disorder><developmental><disseminated lupus erythematosus><drug/agent><eleocolitis><fungus><gain of function><genome mutation><graft versus host disease><graft vs host disease><graft vs. host disease><hCoV19><host response><hypoimmunity><immune deficiency disorder><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immune system response><immunodeficiency><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><improved><inflammatory disease of the intestine><inflammatory disorder of the intestine><inhibitor><insight><interleukin-21><interleukin-4 Stat><intestinal autoinflammation><juvenile arthritis><juvenile idiopathic arthritis><loss of function mutation><myeloproliferative neoplasm><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><p40 Cytokine><p40 Protein><patchy loss of hair><pelade><primary immune deficiency><psoriasiform><psoriatic><regional enteritis><response><rheumatic arthritis><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><skin disorder><systemic lupus erythematosis><tissue repair><viral infection><virus infection><virus-induced disease>