Denver Autoimmunity Center of Excellence

描述（由申请人提供）： 丹佛自身免疫卓越中心（ACE）旨在汇集基础和临床研究人员，研究自身免疫性疾病。项目的目标集中在定义易感基因，阐明免疫发病机制，开发新的疗法，完成新的免疫抑制剂的临床试验，并开发工具，以更好地跟踪自身免疫性疾病的新疗法。丹佛ACE将研究人员的努力与科罗拉多大学健康科学中心的教师任命相结合，该中心与芭芭拉戴维斯儿童糖尿病中心、国家犹太医学和研究中心、内布拉斯加大学医学中心、丹佛医院、落基山多发性硬化症中心和丹佛关节炎诊所有联系。教师已从多个部门和计划，以及内分泌学，风湿病学，临床免疫学，肾脏病学，遗传学，皮肤病学，肺和胃肠病学的子专业招募。有独特的资源，临床研究和强大的基础科学教师，并结合基础和临床研究的跟踪记录。 目前提案的另一个主要优势是丹佛研究T细胞识别和生物学、遗传学以及炎症和细胞因子介导物生物学的工作范围。一个独特的临床资源涉及正在进行的项目，以确定谁是在高风险发展为1型糖尿病的个人。在本申请中，提出的三个基本项目是：（1）确定非MHC基因对人类多发性自身免疫疾病综合征的不同子集的贡献，其似乎作为具有高遗传率的常染色体显性性状遗传;（2）确定补体受体和补体激活在NOD小鼠模型中1型糖尿病的免疫发病机制中的作用;和（3）确定1型干扰素在动物模型中狼疮发病机制中的作用，以及抑制这些细胞因子的作用是否可以预防和抑制疾病表达。在目前的提案中，我们还描述了追求与卓越中心相关的自身免疫性疾病临床研究的多个小组。除了狼疮和狼疮性肾炎的临床试验外，本申请还提出了两项新的临床试验。这两项研究均为II期、随机、双盲和安慰剂对照研究，用于疾病早期患者。 临床项目1研究了使用B 9 -23改变的肽配体来预防糖尿病前期患者临床疾病的发展。临床项目2涉及使用针对CD 20的B细胞特异性单克隆抗体治疗早期类风湿性关节炎（RA）患者。后一个项目涉及与一个独立的机构和一组精通RA临床研究的临床医生的新建立的合作。

DESCRIPTION (provided by applicant): The Denver Autoimmunity Center of Excellence (ACE) aims to bring together basic and clinical investigators for the study of autoimmune diseases. Projects goals focus on defining susceptibility genes, elucidating immunopathogenesis, developing new therapies, accomplishing clinical trials with novel immunotherapeutic agents, and developing tools to better track new therapies in autoimmune disease. The Denver ACE combines the efforts of investigators with faculty appointments at the University of Colorado Health Sciences Center with affiliations with the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, the University of Nebraska Medical Center, hospitals in Denver, the Rocky Mountain Multiple Sclerosis Center, and the Denver Arthritis Clinic. Faculty has been recruited from multiple departments and programs, and the subspecialties of endocrinology, rheumatology, clinical immunology, nephrology, genetics, dermatology, pulmonary, and gastroenterology. There are unique resources for clinical investigation and strong basic science faculty, and a track record for combining basic and clinical investigation. Another major strength of the current proposal is the breadth of work in Denver studying T cell recognition and biology, genetics, and the biology of inflammatory and cytokine mediators. One unique clinical resource relates to ongoing programs to identify individuals who are at high risk to develop type 1 diabetes. In the current application, three proposed basic projects are 1) to define the non-MHC genetic contributions to a distinct subset of human multiple autoimmune disease syndrome, which appears to be inherited as an autosomal dominant trait with high penetrance; (2) to define the role of complement receptors and complement activation in the immunopathogenesis of type 1 diabetes in the NOD mouse model; and (3) to determine the role of type 1 interferons in the pathogenesis of lupus in an animal model, and whether inhibition of the action of these cytokines can prevent and suppress disease expression. In the current proposal, we also describe the multiple groups pursuing clinical investigation of autoimmune disease relevant to the Centers of Excellence. In addition to clinical trials in lupus and lupus nephritis, two new clinical trials are proposed in this application. Both are Phase II, randomized, double blind, and placebo-controlled in patients early in the disease process. Clinical Project 1 investigates the use of a B9-23 altered peptide ligand to prevent the development of clinical disease in patients with pre-diabetes. Clinical project 2 involves the use of a B cell specific monoclonal antibody to CD20 in the treatment of patients with early rheumatoid arthritis (RA). This latter project involves a newly established collaboration with a separate institution and group of clinicians skilled in the clinical investigation of RA.