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Principal Investigator: John O'Shea
Organization: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Fiscal Year: 2024
Award: $282,598
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, psoriatic arthritis, ankylosing spondylitis, SLE, IBD, atopic dermatitis, alopecia areata 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, spondyloarthritis, atopic dermatitis, vitiligo, alopecia areata, psoriasis, Crohn disease, ulcerative colitis and COVID-19. Most recently, it has been established in clinical trials that jakinibs improve the efficacy of checkpoint blockade inhibitors in treatment of cancer.
We previously 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. Other jakinibs are being used in the Clinical Center for lupus and dermatomyositis. Patients with STAT1, STAT4, and STAT6 gain-of-function variants have been successfully 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><Ankylosing spondylitis><Arthritis><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Atrophic Arthritis><Autoimmune Diseases><Axial spondyloarthritis><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><Bechterew Disease><Binding><Binetrakin><Body Tissues><COVID-19><COVID-19 virus><COVID19 virus><CRADA><CV-19><Cancer Treatment><Cardiometabolic Disease><Cardiometabolic Disorder><Cell Differentiation><Cell Differentiation process><Cellular Expansion><Cellular Growth><Chronic Childhood Arthritis><Clinical Trials><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><Coronavirus Infectious Disease 2019><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><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><Lupus Erythematosus Disseminatus><Lymphocyte Mitogenic Factor><Lymphocyte Stimulatory Factor 1><Lymphoid><Lymphopoietin-1><MCGF-2><MGC9721><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Marie-Struempell Disease><Mast Cell Growth Factor-2><Mediating><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><National Institute of Arthritis, and Musculoskeletal, and Skin Diseases><Patents><Pathogenesis><Patients><Phosphotransferase Gene><Phosphotransferases><Polymyositis-Dermatomyositis><Pre-Clinical Model><Preclinical Models><Primary Immunodeficiency><Protein Secretion><Psoriasis><Psoriasis Arthropathica><Psoriatic Arthritis><Receptor Activation><Rheumatoid Arthritis><Rheumatoid Spondylitis><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><Spinal Arthritis><Spondylarthritis><Spondylarthritis Ankylopoietica><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><Variant><Variation><Viral><Viral Diseases><Virus><Virus Diseases><Vitiligo><Wuhan coronavirus><allergic dermatitis><allergic eczema><alopecia circumscripta><antagonism><antagonist><anti-cancer therapy><arthritic><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><autoimmune attack><autoimmune condition><autoimmune destruction><autoimmune disorder><autoimmune pathogenesis><autoimmunity disease><blood cell formation><cancer therapy><cancer-directed therapy><cell growth><cell type><cellular differentiation><check point blockade><checkpoint blockade><clinical center><combined T and B cell inborn immunodeficiency><congenital immune deficiency><congenital immunodeficiency><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><eleocolitis><fungus><gain of function><genetic immune defect><genetic immune deficiency><genetic immunodeficiency><genome mutation><graft versus host disease><graft vs host disease><graft vs. host disease><hCoV19><host response><immune check point blockade><immune checkpoint blockade><immune deficiency disorder><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulatory agents><immune modulatory drugs><immune system response><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><improved><inborn errors in immunity><inborn errors of immunity><inborn immunodeficiency><inflammatory disease of the intestine><inflammatory disorder of the intestine><inherited immune defect><inherited immune deficiency><inherited immunodeficiency><inhibitor><insight><interleukin-21><interleukin-4 Stat><intestinal autoinflammation><juvenile arthritis><juvenile idiopathic arthritis><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 defect><primary immune deficiency><psoriasiform><psoriatic><regional enteritis><response><rheumatic arthritis><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><skin disorder><spondyloarthritis><systemic lupus erythematosis><tissue repair><viral infection><virus infection><virus-induced disease>