University of Michigan Clinical Autoimmunity Center of Excellence

密歇根大学临床自身免疫卓越中心

• 批准号: 9916706
• 负责人: David Alan Fox
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916706
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Cells; Clinical; Clinical Research; Clinical Trials; Clinical effectiveness; Collaborations; Core Facility; Cutaneous; Development; Disease; Disease Pathway; Doctor of Philosophy; Evolution; Faculty; Fibrosis; Fostering; Foxes; Funding; Future; Generations; Home environment; Host Defense; Human; Immune system; Immunologics; Impairment; Inflammation; Institution; Interferons; Janus kinase; Lead; Leadership; Link; Lupus; Lymphocyte; Lymphocyte Subset; Mediating; Michigan; Molecular; Molecular Target; Multiple Sclerosis; National Institute of Allergy and Infectious Disease; Organ; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Photosensitivity; Play; Population; Principal Investigator; Process; Productivity; Proteins; Protocols documentation; Reagent; Research Personnel; Rheumatoid Arthritis; Role; Sampling; Scientist; Scleroderma; Skin; Stromal Cells; Systemic Lupus Erythematosus; Systemic Scleroderma; Translational Research; Universities; Validation; Work; Yang; alanine aminopeptidase; autoimmune thyroid disease; base; biobank; clinical predictors; cohort; cytotoxic; effective therapy; experience; individual patient; insight; keratinocyte; kinase inhibitor; novel; novel marker; novel strategies; patient subsets; personalized medicine; programs; targeted treatment; trial design

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.

摘要 密歇根大学临床ACE目前的工作建立在一个假设的基础上，即器官- 有针对性的自身免疫性疾病依赖于免疫系统细胞之间独特的致病相互作用 以及靶器官的实质或基质细胞，在疾病起始和靶器官破坏中都是如此。 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说， 针对自身免疫性疾病的新的、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洞察而开发：1) 靶器官基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，以及2)本地化的关键作用 自身免疫性疾病患者亚群中靶器官的异常淋巴细胞群，以及 在不对正常宿主防御造成实质性损害的情况下消除这些细胞的机会。 CD319作为治疗系统性硬化症的新靶点的主要临床项目： 由医学博士Dinesh Khanna领导的elotuzumab建立在CD4+CD319+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，这将是第一次 选择治疗人类自身免疫性疾病的受试者的方案 试验进入时靶向淋巴细胞亚群的扩大。替代临床方案：托法替尼治疗 治疗系统性红斑狼疮的光敏性和皮肤炎，由J.Michelle Kahlenberg领导， MD，PhD，基于我们的观察，角质形成细胞衍生的干扰素-kappa驱动光敏和 狼疮皮肤的皮肤炎。用Janus激酶抑制剂治疗这些方面的狼疮 在狼疮中朝着更精确的干扰素-kappa靶向迈出了一步。我们的协作项目：验证 大卫·A·福克斯医学博士领导的更精确治疗自身免疫性疾病的新分子靶点 评估基质细胞产生的选定分子在广泛的靶器官中的表达和功能 自身免疫性疾病的范围--AIRE(自身免疫调节蛋白)、CD318(CD6的新配体)和 CD13可能在人类自身免疫疾病中起着重要的致病作用。这些项目将是 在一个行政核心和一个资金管理核心的支持下，以及在许多患者队列的支持下， 该大学以疾病为重点的临床项目、核心设施和生物库。《校长》 研究人员，Dinesh Khanna博士和David A.Fox博士，在我们现有的临床ACE上密切合作 在系统性硬化症的临床和翻译研究方面拥有丰富的经验和生产力， 类风湿关节炎和其他人类风湿性/自身免疫性疾病。与一组同事一起在 密歇根大学和其他ACE机构的未来合作者，这组调查人员是 准备为我们理解和治疗自身免疫性疾病做出有价值的贡献。