University of Michigan Clinical Autoimmunity Center of Excellence

摘要 密歇根大学临床ACE目前的工作是建立在假设器官- 靶向自身免疫性疾病依赖于免疫系统细胞之间独特的致病性相互作用 和靶器官的实质或基质细胞，在疾病起始和靶器官破坏中。 基于过去五年的进展，我们在这里提出了一个新的但相关的中心假设， 针对自身免疫性疾病的新型、更安全、更有效的精确靶向和个性化治疗， 可以基于对自身免疫性疾病的两个关键和相互作用的组成部分的见解来开发：1） 靶器官间质细胞和实质细胞启动、协调和 控制自身免疫性疾病的演变和后果; 2） 在自身免疫性疾病患者亚群中， 这些细胞的消除没有实质性损害正常的宿主防御的机会。 主要临床项目，CD 319作为系统性硬化症治疗的新靶点： Elotuzumab由Dinesh卡纳，医学博士，理学硕士领导，建立在CD 4 + CD 319+致病作用的证据基础上。 自身免疫性疾病中的淋巴细胞，导致靶器官纤维化。我们相信这将是第一个 基于以下证明选择用于治疗人类自身免疫性疾病的受试者的方案 试验入组时靶向淋巴细胞亚群的扩增。替代临床项目：托法替尼， 治疗系统性狼疮的光敏性和皮肤炎症，由J. Michelle Kahlenberg领导， 医学博士，博士，是基于我们的观察，角质细胞衍生的干扰素κ驱动光敏性， 狼疮皮肤的皮肤炎症。用Janus激酶抑制剂治疗狼疮的这些方面将是可行的。 这是在狼疮中更精确地靶向干扰素κ的一步。我们的合作项目：验证 用于更精确治疗自身免疫性疾病的新分子靶点，由大卫A.福克斯，医学博士，将 评估由基质细胞产生的所选分子在广泛免疫缺陷的靶器官中的表达和功能。 一系列自身免疫性疾病- AIRE（自身免疫调节蛋白），CD 318（CD 6的新型配体）和 CD 13，其可能在人类自身免疫性疾病中具有主要致病作用。这些项目将 由一个行政核心和一个资金管理核心以及众多患者群体支持， 以疾病为重点的临床项目，核心设施和生物储存库在大学。校长 研究人员Dinesh卡纳博士和大卫A. Fox，与我们现有的临床ACE密切合作 并在系统性硬化症的临床和转化研究方面具有丰富的经验和生产力， 类风湿性关节炎和其它人类风湿性/自身免疫性疾病。与一组同事一起， 密歇根大学和其他ACE机构的未来合作者，这组研究人员是 准备为我们理解和治疗自身免疫性疾病做出宝贵的贡献。

Abstract The current work of the University of Michigan Clinical ACE is built on the hypothesis that organ- targeted autoimmune diseases depend on unique pathogenic interactions between cells of the immune system and parenchymal or stromal cells of the target organ, both in disease initiation and target organ destruction. Based on advances over the past five years, we propose here a new but related central hypothesis, that novel, safer and more effective precision-targeted and personalized therapies for autoimmune diseases can be developed based on insights into two critical and interacting components of autoimmune diseases: 1) the molecular mechanisms by which target organ stromal and parenchymal cells initiate, orchestrate and control the evolution and consequences of autoimmune diseases and 2) the critical roles of localization of unusual lymphocyte populations to target organs in subsets of patients with autoimmune diseases, and the opportunity for elimination of these cells without substantial impairment of normal host defenses. The primary clinical project, CD319 as a novel target for treatment of systemic sclerosis: Treatment with Elotuzumab, led by Dinesh Khanna, MD, MSc is built on evidence for a pathogenic role of CD4+CD319+ lymphocytes in autoimmune diseases that leads to fibrosis of target organs. We believe that this will be the first protocol to select subjects for treatment of a human autoimmune disease based on demonstration of expansion of the targeted lymphocyte subset at trial entry. The alternate clinical project: Tofacitinib for treatment of photosensitivity and cutaneous inflammation in systemic lupus, led by J. Michelle Kahlenberg, MD, PhD, is based on our observation that keratinocyte-derived interferon-kappa drives photosensitivity and cutaneous inflammation in lupus skin. Treatment of these aspects of lupus with a janus kinase inhibitor will be a step towards more precise targeting of interferon-kappa in lupus. Our collaborative project: Validation of novel molecular targets for more precise treatment of autoimmune diseases, led by David A. Fox, MD, will assess expression and function of selected molecules produced by stromal cells in target organs of a broad range of autoimmune diseases -- AIRE (the autoimmune regulator protein), CD318 (a novel ligand of CD6) and CD13, which may have major pathogenic roles in human autoimmune conditions. These projects will be supported by an Administrative Core and a Funds Management Core, and by numerous patient cohorts, disease-focused clinical programs, core facilities and biorepositories at the University. The Principal Investigators, Drs. Dinesh Khanna and David A. Fox, work in close collaboration on our existing Clinical ACE and have substantial experience and productivity in clinical and translational research in systemic sclerosis, rheumatoid arthritis and other human rheumatic/autoimmune diseases. Together with a team of colleagues at the University of Michigan and future collaborators from other ACE institutions, this group of investigators is poised to make valuable contributions to our understanding and treatment of autoimmune diseases.