University of Michigan Clinical Autoimmunity Center of Excellence

密歇根大学临床自身免疫卓越中心

基本信息

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
项目类别：
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

项目摘要

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.

抽象的密歇根大学临床ACE目前的工作是基于组织的假设靶向自身免疫性疾病取决于免疫系统细胞之间的独特致病相互作用在疾病起步和靶心器官破坏中，靶器官的实质或基质细胞。根据过去五年的进步，我们在这里提出了一个新的但相关的中心假设，那种针对自身免疫性疾病的小说，更安全，更有效的精确靶向和个性化疗法可以根据对自身免疫性疾病的两个关键和相互作用组成部分的见解开发：1）靶向器官基质和实质细胞启动，编排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子集中靶向器官的不寻常淋巴细胞群体，消除这些细胞的机会，而不会严重损害正常的宿主防御能力。主要的临床项目CD319是治疗系统性硬化症的新靶标：由MD Dinesh Khanna领导的Elotuzumab建立在CD4+CD319+致病作用的证据之上自身免疫性疾病中导致靶器官纤维化的淋巴细胞。我们相信这将是第一个根据证明试验进入时靶向淋巴细胞子集的扩展。替代临床项目：tofacitinib for 由J. Michelle Kahlenberg领导的全身性狼疮的光敏性和皮肤炎症的治疗医学博士，博士是基于我们观察到角质形成细胞衍生的干扰素 - 卡帕驱动光敏性和狼疮皮肤皮肤炎症。用Janus激酶抑制剂对狼疮的这些方面的处理将是朝着更精确的靶向狼疮的kappa迈出的一步。我们的协作项目：验证由大卫·A·福克斯（David A. 评估基质细胞在广泛的靶器官中产生的选定分子的表达和功能自身免疫性疾病范围 - AIRE（自身免疫调节蛋白），CD318（CD6的新型配体）和 CD13，可能在人类自身免疫性条件中具有主要的致病作用。这些项目将是在行政核心和资金管理核心的支持下，并得到许多患者同类的支持该大学以疾病为重点的临床计划，核心设施和生物知名人属。校长调查人员，博士。 Dinesh Khanna和David A. Fox，密切合作在我们现有的临床ACE上并具有在系统性硬化症的临床和转化研究中具有丰富的经验和生产力，类风湿关节炎和其他人类风湿/自身免疫性疾病。以及一个同事团队密歇根大学和其他ACE机构的未来合作者，这组调查员是准备为我们对自身免疫性疾病的理解和治疗做出宝贵的贡献。