Targeting Janus kinases in the treatment of autoimmune disease

细胞因子包括一个大的家族分泌的蛋白质，调节细胞生长和分化的许多类型的细胞。这些因素在调节免疫和炎症反应以及调节淋巴细胞的发育和分化中尤为重要。毫不奇怪，细胞因子在许多自身免疫性疾病如类风湿关节炎、SLE、IBD和牛皮癣的发病机制中起着至关重要的作用。了解细胞因子作用的分子基础为了解免疫介导疾病的发病机制提供了重要的见解，并提供了新的治疗靶点。

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. 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 developed 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, IBD and various dermatological conditions. Several other Jakinibs have been developed and are also in clinical trials, including late phase pivotal 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 that SLE might be an appropriatecandidate for this class of drugs. 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 other interferons. The action of these cytokines are all blocked by first generation Jakinibs like tofacitinib. In addition, immune cell dysregulation in SLE is also associated with premature vascular damage. To 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 in terms of both 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 improve vascular function. These results indicate that JAKinibs have the potential to be beneficial in treating SLE and its associated vascular damage in humans. Based on these favorable findings, we have begun a clinical trial of tofacitinib in mild-moderate SLE at the NIH Clinical Center. In related work in cancer, we collaborated on work with a Jakinib in Adult T-cell leukemia (ATL), a disease caused by infection with HTLV1 associated with constitutive activation of the Jak/STAT pathway. 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) activates autocrine/paracrine interleukin-2 (IL-2), IL-9, and IL-15 production, resulting in amplified JAK/STAT signaling. The selective Jakininb ruxolitinib was examined in a high-throughput matrix screen combined with greater than 450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. 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. In related studies, devoted to better understanding the mechanism of action of tofacitinib, we examined its effect on the evolving enhancer landscapes of activated T cells. We found that tofacitinib has a selective effect on super-enhancers compared to typical enhancers. Finally, we collaborated with external investigators to identify new potential targets that affect Th17 cells.