Targeting Jak3 in the treatment of autoimmune disease

细胞因子组成一个分泌蛋白大家族，调节细胞生长和多种类型细胞的分化。这些因子在调节免疫和炎症反应、调节淋巴样细胞的发育和分化方面尤为重要。毫不奇怪，细胞因子在类风湿性关节炎、系统性红斑狼疮、炎症性肠病和牛皮癣等自身免疫性疾病的发病机制中起着关键作用。了解细胞因子作用的分子基础有助于深入了解免疫介导性疾病的发病机制，并提供新的治疗靶点。 我们发现了人类JAK3，一种通过结合共同伽马链的细胞因子GC(IL-2、IL-4、IL-7、IL-9、IL-15和IL-21)进行信号传递所必需的激酶。我们发现JAK3的突变会导致一种称为严重联合免疫缺陷(SCID)的原发性免疫缺陷疾病。我们已经获得了两项与将JAK3作为新型免疫抑制/免疫调节药物基础的专利，并与辉瑞公司建立了合作研究和开发协议(CRADA)，以产生第一代JAK3拮抗剂。一种名为tofacitinib(CP 690,550)的化合物由辉瑞公司生产，并被发现在临床前模型中有效。该药物在类风湿性关节炎的第三阶段研究中进行了测试，现在已被批准用于这一适应症。托法替尼还被用于治疗牛皮癣、牛皮癣关节炎、强直性脊柱炎、青少年关节炎和移植排斥反应。其他几种JAK抑制剂已经开发出来，也在进行临床试验。 今年与辉瑞公司续签了CRADA，旨在更好地了解tofacitinib和相关抑制剂的作用机制。目前的研究正在进行中，评估托法替尼在移植物抗宿主病模型中的作用。尽管异基因造血干细胞移植(HSCT)取得了成功，但并发症移植物抗宿主病(GvHD)仍然是导致发病率和死亡率的重要原因。对这种不同的疾病集合进行适当的治疗是一个尚未得到满足的需求，在这种情况下可能会使用JAK抑制剂。我们一直在研究托法替尼对CD8T细胞依赖的GvHD小鼠模型的影响，在该模型中，角蛋白14启动子-鸡卵清蛋白(OVA)转基因小鼠过继转移表达OVA特异性T细胞受体的CD8T细胞(OT-I细胞)。我们发现口服tofacitinib完全预防了GvHD样疾病；更重要的是，tofacitinib在逆转已建立的GvHD样疾病方面也是有效的。用托法替尼治疗受影响的小鼠可减少OT-I效应细胞的数量。这种治疗还减少了细胞因子和趋化因子的产生，以及转移的T细胞中的激活标志。这些数据提示托法替尼在治疗移植物抗宿主病方面可能是有效的。此外，这些数据还证明了其他CD8介导的免疫介导性疾病的潜在用途。 此外，我们正在研究托法替尼对T细胞代谢的影响。T细胞的激活与糖酵解代谢的转换有关。我们发现托法替尼抑制了许多关键的糖酵解酶的诱导。干扰细胞因子调节的代谢变化可能是JAK抑制剂作用机制的一个重要方面。

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 Jak3 antagonists. One compound, tofacitinib (CP 690,550), was produced by Pfizer and found to be effective in preclinical models. The drug was tested in Phase III studies 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 this year and was directed at better understanding the mechanisms of action of tofacitinib and related inhibitors. Current studies are ongoing, evaluating tofacitinib in models of graft versus host disease. Despite the success of allogeneic hematopoietic stem cell transplantation (HSCT), the complication graft versus host disease (GvHD) remains a significant cause of morbidity and mortality. Adequate treatment of this heterogeneous collection of disorders is an unmet need, and Jak inhibitors might be used in this setting. We have been studying the effects of tofacitinib on a CD8 T-cell-dependent murine model of GvHD, in which keratin 14 promoter-chicken ovalbumin (OVA)-transgenic mice adoptively transferred with CD8 T cells expressing an OVA-specific T cell receptor (OT-I cells). We found that oral administration of tofacitinib completely prevented the GvHD-like disease; more importantly, tofacitinib was also effective in reversing established GvHD-like disease. Treatment of affected mice with tofacitinib diminished the number of OT-I effector cells. This treatment also reduced cytokine and chemokine production, and markers of activation in transferred T cells. These data suggest that tofacitinib may be of utility in the treatment of GvHD. In addition, the data argue for the potential use of other CD8-mediated immune-mediated disorders. In addition, we are studying the effects of tofacitinib on T cell metabolism. T cell activation is associated with a switch to glycolytic metabolism. We have found that tofacitinib inhibits the induction of many key glycolytic enzymes. The interference with cytokine-regulated changes in metabolism may be an important aspect of the mechanism of action of Jak inhibitors.