Targeting Janus kinases in the treatment of autoimmune disease

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

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Abstract

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 appropriate candidate 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. In view of these results, NIAMS has launched a clinical trial of tofacitinib in mild-moderate SLE at the NIH Clinical Center. The enrollment of this clinical is presently underway. To better understand the implications of the use of first and second generation jakinibs, we are presently studying their effects on the homeostasis of innate lymphoid cells in murine models.