University of Michigan Autoimmunity Center of Excellence, Clinical Research Progr

密歇根大学自身免疫卓越中心临床研究项目

• 批准号: 9480038
• 负责人: David Alan Fox
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9480038
• 关键词: Advisory Committees; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Award; Boston; Cells; Characteristics; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical effectiveness; Core Facility; Development; Diabetes Mellitus; Disease; Disease Pathway; Doctor of Philosophy; Epidemiology; Faculty; Fibrosis; Fostering; Foxes; Funding; Grant; Host Defense; Human; Immune; Immune Cell Activation; Immune system; Immunologics; Immunosuppressive Agents; Link; Lymphocyte; Mediating; Michigan; Multiple Sclerosis; National Institute of Allergy and Infectious Disease; Neuraxis; Organ; Pathogenesis; Pathogenicity; Patients; Pharmaceutical Preparations; Play; Process; Reagent; Recovery; Research Personnel; Research Project Grants; Rheumatoid Arthritis; Role; Scleroderma; Secondary Progressive Multiple Sclerosis; Skin; Sphingosine-1-Phosphate Receptor; Systemic Scleroderma; T-Lymphocyte; Translational Research; United States National Institutes of Health; Universities; Work; Yang; autoimmune thyroid disease; autoreactive T cell; clinical predictors; cytotoxic; effective therapy; experience; individual patient; insight; multidisciplinary; novel; novel marker; novel strategies; phase 3 study; phase III trial; programs; repaired; tissue biomarkers; translational scientist; trial design

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.

描述（由申请人提供）：该临床ACE应用是由以下假设驱动的：器官靶向自身免疫性疾病由免疫系统细胞与靶器官实质细胞之间的独特致病性相互作用介导，其在疾病发生和靶器官破坏中起传入和传出作用。通过了解这些疾病特异性过程，疾病特异性治疗的新途径应该进入视野，沿着新的生物标志物，反映淋巴细胞和靶器官细胞之间的疾病特异性相互作用。这一假设是本临床ACE的三个拟议项目的基础。 主要临床项目：“BAF 312治疗继发性进展性多发性硬化症的III期临床试验的机制研究”，由Yang Mao-Draayer博士和Benjamin M. Segal博士将研究一种新型鞘氨醇-1-磷酸受体调节剂的临床获益机制，重点关注MS的致病性T细胞自身反应性特征，以及受损中枢神经系统启动免疫攻击修复和恢复的能力。 替代临床项目：由医学博士Dinesh卡纳和共同研究者大卫A福克斯（医学博士）、医学博士Robert Lafyatis（波士顿大学）和博士Michael Whitfield（达特茅斯）领导的“阿巴西普治疗系统性硬化症的机制研究”将评估硬皮病中T细胞共刺激阻断对免疫细胞活化以及皮肤中组织损伤和纤维化的生物标志物的影响。 合作项目：“器官特异性实质细胞在人类器官靶向自身免疫性疾病中的作用”，由Massimo Pietropaolo，医学博士和共同研究者大卫A。Fox，医学博士，Roberto Gianani，医学博士和Terry J. Smith，医学博士将研究可能参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，三种聚集流行病学的疾病的启动的靶器官现象。 行政核心和整个项目将由大卫A。Fox博士，他在指导多学科NIH资助的中心赠款方面有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伤的相关但不同的机制，将开发新的方法来理解和治疗人类自身免疫。

项目成果

Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity.

• DOI: 10.1177/1352458520937282
• 发表时间: 2021-05
• 期刊: Multiple sclerosis (Houndmills, Basingstoke, England)
• 作者: Longbrake EE;Mao-Draayer Y;Cascione M;Zielinski T;Bame E;Brassat D;Chen C;Kapadia S;Mendoza JP;Miller C;Parks B;Xing D;Robertson D
• 通讯作者: Robertson D

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients.

• DOI: 10.4049/jimmunol.1601532
• 发表时间: 2017-04-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wu Q;Wang Q;Mao G;Dowling CA;Lundy SK;Mao-Draayer Y
• 通讯作者: Mao-Draayer Y

Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

与结节病相关的进行性多灶性白质脑病的特征，无需治疗性免疫抑制。

• DOI: 10.1001/jamaneurol.2023.0841
• 发表时间: 2023
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: McEntire,CalebRS;Fletcher,Anita;Toledano,Michel;Epstein,Samantha;White,Emily;Tan,CSabrina;Mao-Draayer,Yang;Banks,SamanthaA;Aksamit,AllenJ;Gelfand,JeffreyM;Thakur,KiranT;Anand,Pria;Cortese,Irene;Bhattacharyya,Shamik
• 通讯作者: Bhattacharyya,Shamik

Safety and Immune Effects of Blocking CD40 Ligand in Multiple Sclerosis.

• DOI: 10.1212/nxi.0000000000001096
• 发表时间: 2021-11
• 期刊: Neurology(R) neuroimmunology & neuroinflammation
• 作者: Fadul CE;Mao-Draayer Y;Ryan KA;Noelle RJ;Wishart HA;Channon JY;Kasper IR;Oliver B;Mielcarz DW;Kasper LH
• 通讯作者: Kasper LH

Synovial cellular and molecular markers in rheumatoid arthritis.

• DOI: 10.1007/s00281-017-0631-3
• 发表时间: 2017-06
• 期刊: Seminars in immunopathology
• 影响因子: 9
• 作者: Asif Amin M;Fox DA;Ruth JH
• 通讯作者: Ruth JH