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, regulating lymphoid development and differentiation. Not surprisingly, cytokines are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and psoriasis. 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 immunosuppressant/immunomodulatory drugs, and established a Cooperative Research and Development Agreement (CRADA) with Pfizer to generate the first-generation Jak antagonists. One compound, tofacitinib,, was produced by Pfizer and found to be effective in preclinical models. The drug was tested in rheumatoid arthritis, and has now been approved for this indication. Tofacitinib is also being studied in psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile arthritis and transplant rejection. Several other Jak inhibitors have been developed and are also in clinical trials. The CRADA with Pfizer was renewed and is directed at better understanding the mechanisms of action of tofacitinib and related inhibitors. In considering other clinical circumstances in which Jakinibs might be useful, we considered a graft-versus-host-disease as an unmet need in which this agent would be effective. In a murine model of GVHD-like disease, we showed that tofacitinib was effective in preventing and reversing disease. We also investigated the potential utility of Jakinibs in the setting of cancer therapy. Specifically, we showed that tofacitinb limited host response antibody responses to immunotoxins. This finding is of potential significance not only for immunotoxins and cancer but also other settings in which protein therapeutics are used. In related work in cancer, we studied the effect of a Jakinib in Adult T-cell leukemia (ATL) which is caused by infection with HTLV1. This is an important unmet need as presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates activates autocrine/paracrine interleukin-2, (IL-2), IL-9, and IL-15 autocrine/paracrine production, resulting in amplified JAK/STAT signaling. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents,and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate formulticomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL. Given the widespread utility of anti-cancer drugs in autoimmune disease (e.g. methotrexate), the results raise the possibility of this combination therapy in immune-mediated disease. As prelude for considering the potential utility of tofacitinib and other Jakinibs in systemic lupus erythematosus, we set out to investigate this possibility in a mouse model of lupus. A number of cytokines that impact both innate and adaptive immunity have been suggested to contribute to the immunopathogenesis of SLE including interferons, IL-6, IL-21, and others. The action of these cytokines can by blocked by Jakinibs. In addition, immune cell dysregulation in SLE is also associated premature vascular damage. To this date, no drug has proven to target both disease activity and enhanced cardiovascular risk in SLE. We therefore set out to assess whether tofacitinib might have utility in SLE both in terms of immune cell dysfunction and vascular damage. We found that treatment with tofacitinib led to improvement in nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment significantly reduced serum levels of relevant cytokines. Tofacitinib also modulated neutrophil dysfunction and endothelial abnormalities. Thus, we concluded that tofacitinib can modulate the innate and adaptive immune responses in murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE in humans and its associated vascular damage. In related studies, devoted to better understanding the mechanism of action of tofacitinib, we examined its on the evolving enhancer landscapes of activated T cells. We found that tofacitinib has a selective effect on stretch/super enhancers compared to typical enhancers. Finally, we collaborated with external investigators to identify new potential targets that affect Th17 cells.
| Gadina, Massimo; Johnson, Catrina; Schwartz, Daniella et al. (2018) Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol 104:499-514 |
| Schwartz, Daniella M; Kanno, Yuka; Villarino, Alejandro et al. (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17:78 |
| Furumoto, Yasuko; Smith, Carolyne K; Blanco, Luz et al. (2017) Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction. Arthritis Rheumatol 69:148-160 |
| Villarino, Alejandro V; Kanno, Yuka; O'Shea, John J (2017) Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18:374-384 |
| Shih, Han-Yu; Sciumè, Giuseppe; Mikami, Yohei et al. (2016) Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality. Cell 165:1120-1133 |
| Hirahara, Kiyoshi; Schwartz, Daniella; Gadina, Massimo et al. (2016) Targeting cytokine signaling in autoimmunity: back to the future and beyond. Curr Opin Immunol 43:89-97 |
| Gadina, Massimo; Schwartz, Daniella M; O'Shea, John J (2016) Decernotinib: A Next-Generation Jakinib. Arthritis Rheumatol 68:31-4 |
| Schwartz, Daniella M; Bonelli, Michael; Gadina, Massimo et al. (2016) Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 12:25-36 |
| O'Shea, John J; Schwartz, Daniella M; Villarino, Alejandro V et al. (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 66:311-28 |
| Villarino, Alejandro V; Kanno, Yuka; Ferdinand, John R et al. (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21-7 |
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