Targeting Janus kinases in the treatment of autoimmune disease

靶向 Janus 激酶治疗自身免疫性疾病

• 批准号: 10265198
• 负责人: John O'Shea
• 金额: $ 35.45万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265198
• 关键词: Affect; Alopecia Areata; Ankylosing spondylitis; Apoptosis; Arthritis; Asthma; Atherosclerosis; Atopic Dermatitis; Autoantibodies; Autoimmune Diseases; BCL2 gene; Bacteria; Binding; Blood Vessels; Bone Marrow; Cell Cycle; Cells; Cholesterol; Chronic Childhood Arthritis; Clinical; Clinical Trials; Collaborations; Controlled Clinical Trials; Cooperative Research and Development Agreement; Cytokine Signaling; Dermatologic; Development; Differentiation and Growth; Disease; Double-Blind Method; Endothelium; Event; Family; Functional disorder; Generations; Genes; Goals; Growth and Development function; Hematopoiesis; High Density Lipoproteins; Homeostasis; Host Defense; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunomodulators; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Interferon Type I; Interferons; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-6; Interleukin-7; Interleukin-9; Janus kinase; Laboratories; Legal patent; Link; Liver; Longitudinal Studies; Lupus; Lymphoid; Lymphoid Cell; Mediating; Metabolism; Molecular; Mus; Mutation; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural Immunity; Natural Killer Cells; Nephritis; Opportunistic Infections; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phosphatidylcholine-Sterol O-Acyltransferase; Phosphorylation; Phosphotransferases; Placebos; Pre-Clinical Model; Production; Proteins; Psoriasis; Psoriatic Arthritis; Randomized; Receptor Activation; Rheumatoid Arthritis; STAT4 gene; Serum; Severe Combined Immunodeficiency; Skin; Spleen; Systemic Lupus Erythematosus; Testing; Tissues; United States National Institutes of Health; Virus; Withdrawal; adaptive immune response; adaptive immunity; arterial stiffness; base; cardiometabolism; cardiovascular risk factor; cell growth; cell type; clinical center; clinically relevant; congenital immunodeficiency; cytokine; density; endothelial dysfunction; extracellular; fungus; genetic signature; granulocyte; improved; inhibitor/antagonist; insight; liver function; mouse model; neutrophil; new therapeutic target; particle; placebo group; pre-clinical; premature; risk variant; skin disorder; tissue repair; transcriptome; treatment group

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 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. Tofacitinib is now approved for rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Tofacitinib and other Jak inhibitors (jakinibs) are also being studied in ankylosing spondylitis, juvenile arthritis, and many dermatological conditions including psoriasis, alopecia areata and atopic dermatitis. 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. 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. In a preclinical model, 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. Based on these preclinical findings, in collaboration with the Kaplan lab and the NIAMS Lupus Clinical Trials clinical trial in mild-moderate SLE was launched at the NIH Clinical Center. This phase 1b/2a randomized, double-blind, placebo-controlled clinical trial of using tofacitinib in 30 SLE subjects (2:1 drug to placebo ratio) was stratified by the presence or absence of STAT4 risk allele. This study showed the type I Interferon gene signature, circulating levels of low-density granulocytes and neutrophil extracellular traps significantly decreased in the tofacitinib treated group compared to the placebo group by day 56, accompanied by significant decreases in pSTAT phosphorylation of different immune cells. The use of tofacitinib resulted in a significant increase in HDL-C and HDL particle number in tofacitinib-treated patients accompanied by significant improvements in lecithin: cholesterol acyltransferase (LCAT) concentration and cholesterol efflux capacity. Arterial stiffness and endothelial dysfunction improved in the treatment group as compared to the placebo group. Most of these changes reverted towards baseline values at the end of study, 4 weeks after withdrawal of tofacitinib. Some of these changes were associated to presence or absence of STAT4 risk allele. In addition, tofacitinib was well tolerated with no worsening of SLE disease activity, no severe AEs, opportunistic infections, thromboembolic events or liver function abnormalities. Thus, in a short-term trial, use of tofacitinib resulted in significant improvements in cardiometabolic and immunologic disease parameters associated with accelerated atherosclerosis in SLE. Long-term studies are needed to determine the efficacy of tofacitinib in the various manifestations of SLE including cardiovascular risk. To better understand the implications of the use of first and second generation jakinibs, especially in inflammatory bowel disease, the effects these agents on the homeostasis of adaptive and innate lymphoid cells in murine models was also investigated. We found that in mice treated with jakinibs, the homeostatic pool of liver ILC1 was less affected compared to the pool of NK cells present in the liver, spleen and bone marrow. JAK inhibition had overlapping effects on the transcriptome of both subsets, mainly affecting genes regulating cell cycle and apoptosis. However, the differential impact of JAK inhibition was linked to the high levels of the antiapoptotic gene Bcl2 expressed by ILC1. Our findings provide mechanistic explanations for the effects of JAK inhibitors on NK cells and ILC1 which could be of major clinically relevance.

细胞因子包括一个大型分泌的蛋白质家族，这些蛋白质调节了许多类型的细胞的细胞生长和分化。这些因素在调节免疫和炎症反应以及调节淋巴发育和分化方面尤为重要。毫不奇怪，细胞因子对于许多自身免疫性疾病（例如类风湿关节炎，SLE，IBD和牛皮癣）的发病机理至关重要。了解细胞因子作用的分子基础为免疫介导疾病的发病机理提供了重要的见解，并提供了新的治疗靶标。 我们发现了人类JAK3，这是一种通过结合共同伽马链（IL-2，IL-4，IL-7，IL-7，IL-9，IL-9，IL-15和IL-21）的细胞因子信号传导所必需的激酶。我们发现JAK3的突变导致原发性免疫缺陷障碍称为严重的免疫缺陷（SCID）。我们已经获得了针对JAK3作为新的免疫调节药物的基础的两项专利，并与Pfizer建立了合作研究与发展协议（CRADA），以产生第一代JAK对手。一种化合物，tofacitinib是由辉瑞开发的，发现在临床前模型中有效。 Tofacitinib现在被批准用于类风湿关节炎，银屑病关节炎和炎症性肠病。 tofacitinib和其他JAK抑制剂（jakinibs）也在强直性脊柱炎，少年关节炎以及许多皮肤病学疾病中进行了研究，包括牛皮癣，毛虫果皮和特应性皮肤炎。已经开发了其他几种jakinib，并且还在临床试验中，包括晚期关键试验。 与辉瑞的Crada进行了更新，并指向更好地理解tofacitinib和相关抑制剂的作用机理。在考虑其他可能有用的jakinibs的临床情况下，我们认为SLE可能是这类药物的合适候选者。已经提出了许多影响先天和适应性免疫的细胞因子，以有助于SLE的免疫发病发生，包括干扰素IL-6，IL-21和其他干扰素。另外，SLE中的免疫细胞失调也与早产血管损伤有关。迄今为止，尚无证明针对疾病活动和SLE中心血管风险增强的药物。在临床前模型中，我们发现用tofacitinib治疗导致肾炎，皮肤炎症和自身抗体的产生改善。此外，tofacitinib治疗显着降低了相关细胞因子的血清水平。 Tofacitinib还调节中性粒细胞功能障碍和内皮异常。因此，我们得出的结论是，tofacitinib可以调节鼠狼疮中的先天和适应性免疫反应并改善血管功能。基于这些临床前发现，在NIH临床中心与Kaplan Lab和Niams Lupus临床试验临床试验合作。该阶段1b/2a随机，双盲，安慰剂对照的临床试验，在30名SLE受试者中使用Tofacitib（2：1药物与安慰剂比率），通过存在或不存在STAT4风险等位基因来分层。这项研究表明，与安慰剂组相比，与安慰剂组相比，在Tofacitinib治疗组中，低密度粒细胞的循环水平，低密度粒细胞的循环水平和中性粒细胞外陷阱显着降低，伴随着不同免疫细胞PSTAT磷酸化的显着降低。 Tofacitinib的使用导致tofacitinib治疗的患者的HDL-C和HDL颗粒数显着增加，并伴随着卵磷脂的显着改善：胆固醇酰基转移酶（LCAT）浓度和胆固醇外排能力。与安慰剂组相比，治疗组的动脉刚度和内皮功能障碍改善了。这些变化大多数在研究结束时恢复了基线值，即tofacitinib撤离后4周。 其中一些变化与STAT4风险等位基因的存在或不存在有关。此外，Tofacitinib的耐受性良好，没有SLE疾病活性的恶化，没有严重的AE，机会性感染，血栓栓塞事件或肝功能异常。因此，在一项短期试验中，使用tofacitinib导致与SLE中与加速动脉粥样硬化有关的心脏代谢和免疫疾病参数的显着改善。需要长期研究来确定tofacitib在SLE的各种表现中的功效，包括心血管风险。 为了更好地理解第一和第二代jakinibs使用的含义，尤其是在炎症性肠病中，还研究了这些药物对鼠模型中适应性和先天淋巴样细胞体内稳态的影响。 我们发现，在用jakinibs治疗的小鼠中，与肝脏，脾脏和骨髓中存在的NK细胞库相比，肝脏ILC1的体内平衡库受到的影响较小。 JAK抑制对两个子集的转录组都有重叠的影响，主要影响调节细胞周期和凋亡的基因。然而，JAK抑制的差异影响与ILC1表达的抗凋亡基因BCl2的高水平有关。我们的发现为JAK抑制剂对NK细胞和ILC1的影响提供了机械解释，这在临床上可能具有很大的相关性。