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: 10662184
• 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/10662184
• 关键词: Activated-Leukocyte Cell Adhesion Molecule; Articulation; Autoimmune; Autoimmune Diseases; 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; Frustration; Funding; Future; Generations; Home; Host Defense; Human; Immune system; Immunologics; Immunosuppressive Agents; Impairment; Inflammation; Institution; Interferons; Janus kinase; 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; Precision therapeutics; Principal Investigator; Process; Productivity; Proteins; Protocols documentation; Reagent; Research Personnel; Rheumatoid Arthritis; Role; Scientist; Scleroderma; Skin; Stromal Cells; Subjects Selections; Systemic Lupus Erythematosus; Systemic Scleroderma; Translational Research; Universities; Validation; Work; alanine aminopeptidase; autoimmune inflammation; autoimmune thyroid disease; biobank; clinical predictors; clinical translation; 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.

抽象的 密歇根大学临床 ACE 目前的工作建立在以下假设之上：器官 靶向自身免疫性疾病取决于免疫系统细胞之间独特的致病相互作用 以及靶器官的实质细胞或基质细胞，无论是在疾病发生还是靶器官破坏中。 基于过去五年的进展，我们在此提出一个新的但相关的中心假设， 针对自身免疫性疾病的新颖、更安全、更有效的精准靶向和个性化疗法 可以基于对自身免疫性疾病两个关键且相互作用的组成部分的深入了解而开发：1) 靶器官基质细胞和实质细胞启动、协调和调节的分子机制 控制自身免疫性疾病的演变和后果，2）定位的关键作用 自身免疫性疾病患者亚群中异常的淋巴细胞群瞄准器官，以及 消除这些细胞的机会，而不会严重损害正常宿主的防御。 主要临床项目，CD319作为治疗系统性硬化症的新靶点：治疗 Elotuzumab 由医学博士、理学硕士 Dinesh Khanna 领导，建立在 CD4+CD319+ 致病作用的证据之上 自身免疫性疾病中的淋巴细胞会导致靶器官纤维化。我们相信这将是第一个 根据证明选择治疗人类自身免疫性疾病受试者的方案 在试验进入时扩大目标淋巴细胞亚群。替代临床项目：托法替尼（Tofacitinib） 由 J. Michelle Kahlenberg 领导的治疗系统性狼疮的光敏性和皮肤炎症， MD、PhD 是基于我们的观察，即角质形成细胞衍生的干扰素 kappa 驱动光敏性和 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 朝着更精确地靶向狼疮中的干扰素-κ迈出的一步。我们的合作项目：验证 由医学博士 David A. Fox 领导的用于更精确治疗自身免疫性疾病的新分子靶标将 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 一系列自身免疫性疾病——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疾病中具有主要致病作用。这些项目将 在行政核心和资金管理核心以及众多患者群体的支持下， 大学以疾病为中心的临床项目、核心设施和生物样本库。校长 研究人员，博士。 Dinesh Khanna 和 David A. Fox 密切合作开发我们现有的 Clinical ACE 在系统性硬化症的临床和转化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/自身免疫性疾病。与同事团队一起 密歇根大学和其他 ACE 机构未来的合作者，这组研究人员是 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。

项目成果

Case report: IgG4-related intracranial lesions mimicking multiple sclerosis in a 14-year-old girl.

• DOI: 10.3389/fneur.2022.1007153
• 发表时间: 2022
• 期刊: Frontiers in neurology
• 影响因子: 3.4

Immunodeficiency and autoimmunity: companions not opposites.

• DOI: 10.1172/jci162170
• 发表时间: 2022-08-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: Fox, David A.

The dual role of CD6 as a therapeutic target in cancer and autoimmune disease.

• DOI: 10.3389/fmed.2022.1026521
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9

Genetic association and single-cell transcriptome analyses reveal distinct features connecting autoimmunity with cancers.

• DOI: 10.1016/j.isci.2022.104631
• 发表时间: 2022-07-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Li, Shasha;Lu, Chenyang;Zhang, Yuan;Zhao, Xiaolu;Lin, Kequan;Kong, Xiufang;Fox, David;Xue, Lixiang;Sun, Lichao;Liu, Yi;Mao, Fengbiao
• 通讯作者: Mao, Fengbiao