University of Michigan Autoimmunity Center of Excellence, Clinical Research Progr

描述(申请人提供)：这项临床ACE申请是基于这样一种假设，即针对器官的自身免疫疾病是由免疫系统的细胞和目标器官的实质细胞之间独特的致病相互作用所介导的，免疫系统细胞和目标器官的实质细胞在疾病启动和目标器官破坏中扮演传入和传出的角色。通过了解这些疾病特异性的过程，应该可以看到疾病特异性治疗的新途径，以及反映淋巴细胞和靶器官细胞之间疾病特异性相互作用的新生物标记物。这一假设构成了这项临床ACE的三个拟议项目的基础。 初级临床项目：由医学博士杨茂德拉耶和医学博士本杰明·M·西格尔领导的“使用BAF312治疗继发性进行性多发性硬化症的第三阶段试验的机制研究”，将研究一种新型的鞘氨醇-1-磷酸受体调节剂的临床益处机制，重点是多发性硬化症的致病T细胞自身反应特性，以及受损的中枢神经系统启动修复和从免疫攻击中恢复的能力。 另一个临床项目：由医学博士Dinesh Khanna、医学博士David A Fox、波士顿大学医学博士Robert Lafyatis和达特茅斯大学博士Michael Whitfield共同领导的“用abatacept治疗系统性硬化症的机制研究”，将评估在硬化症中阻断T细胞共刺激对免疫细胞激活以及皮肤组织损伤和纤维化的生物标记物的影响。 由医学博士Massimo Pietropaolo领导、医学博士David A.Fox、医学博士Roberto Gianani和医学博士Terry J.Smith领导的“器官特定实质细胞在人类器官定向自身免疫疾病中的作用”合作项目将研究可能与自身免疫性糖尿病、类风湿性关节炎和自身免疫性甲状腺疾病相关的靶器官现象，这三种疾病在流行病学上是聚集的。 行政核心和整体项目将由大卫·A·福克斯医学博士领导，他在指导NIH资助的多学科中心拨款方面有20年的经验。 相关性：密歇根大学临床ACE通过将多发性硬化症、硬皮病、糖尿病、类风湿性关节炎和自身免疫性甲状腺疾病方面的经验丰富的研究人员联系起来，探索这些条件下靶器官损害的相关但不同的机制，将开发了解和治疗人类自身免疫的新方法。

DESCRIPTION (provided by applicant): This Clinical ACE application is driven by the hypothesis that organ-targeted autoimmune diseases are mediated by unique pathogenic interactions between cells of the immune system and parenchymal cells of the target organ, which play both afferent and efferent roles in disease initiation and target organ destruction. By understanding these disease-specific processes, new avenues to disease-specific treatment should come into view, along with novel biomarkers that reflect disease-specific interactions between lymphocytes and cells of the target organ. This hypothesis underlies the three proposed projects of this Clinical ACE. The Primary Clinical Project: "Mechanistic studies of Phase III trial with BAF312 in Secondary Progressive Multiple Sclerosis", led by Yang Mao-Draayer, PhD, MD and Benjamin M. Segal, MD, will study the mechanisms of clinical benefit of a novel sphingosine-1-phosphate receptor modulator, focusing both on pathogenic T cell autoreactivity characteristic of MS, and on the ability of the damaged central nervous system to initiate repair and recovery from immune attack. The Alternate Clinical Project: "Mechanistic studies of treatment of systemic sclerosis with Abatacept", led by Dinesh Khanna, MD, MS, with co-investigator David A Fox, MD, Robert Lafyatis, MD (Boston U), and Michael Whitfield, PhD (Dartmouth), will assess the effects of T cell co-stimulation blockade in scleroderema on both immune cell activation, and biomarkers of tissue damage and fibrosis in the skin. The Collaborative Project: "Role of organ-specific parenchymal cells in human organ-targeted autoimmune diseases", led by Massimo Pietropaolo, MD, with co-investigators David A. Fox, MD, Roberto Gianani, MD, and Terry J. Smith, MD, will study target organ phenomena potentially involved in the initiation of autoimmune diabetes, rheumatoid arthritis and autoimmune thyroid disease, three conditions that cluster epidemiologically. The Administrative Core and overall project will be led by David A. Fox, MD, who has two decades of experience in directing multidisciplinary NIH-funded center grant awards. RELEVANCE: The University of Michigan Clinical ACE, by linking experienced investigators in multiple sclerosis, scleroderma, diabetes, rheumatoid arthritis and autoimmune thyroid disease in the exploration of related yet distinct mechanisms of target organ damage in these conditions, will develop new approaches to understanding and treating human autoimmunity.