DENVER AUTOIMMUNITY CENTER OF EXCELLENCE

拟建的丹佛自身免疫卓越中心结合了科罗拉多大学健康科学中心的研究人员和教职人员的努力。附属机构包括芭芭拉·戴维斯儿童糖尿病中心、国家犹太医学和研究中心、丹佛儿童医院、丹佛大学医院、落基山多发性硬化症中心以及丹佛关节炎诊所。我们的师资队伍来自免疫学、儿科、医学、神经病学、皮肤病学、病理学、预防医学/流行病学和人类医学遗传学项目。在儿科和医学部，亚专科包括内分泌学、风湿病学、临床免疫学、肾脏病学、肺病和胃肠病学。有独特的临床研究资源和强大的基础师资，在许多情况下，基础和临床研究相结合的记录。拟建的自身免疫中心包括1型糖尿病、乳糜泻、系统性狼疮、类风湿关节炎、多发性硬化症、自身免疫性皮肤病、自身免疫性肺部疾病以及其他自身免疫性疾病的强大研究和临床基础。一个独特的临床资源涉及正在进行的新生儿研究，这些研究来自一般人群和HLA分型的1型糖尿病患者的亲属，然后使用脐带血前瞻性地评估与1A型糖尿病和疾病相关的自身抗体的发展。我们认为，当前提案的主要优势在于丹佛研究T细胞识别和生物学、遗传学以及炎症和细胞因子介质生物学的广度。在目前的提案中，提出了两项临床试验。临床项目1将评估皮下胰岛素疫苗接种，以防止自身抗体和疾病发展高风险婴儿出现抗胰岛自身抗体。临床项目2将在活动性狼疮性肾炎患者中测试人源化抗c5单克隆抗体。提出的三个基本组成部分是：1)确定胰岛素和胰岛抗原反应性T细胞在小鼠模型和1型患者中的特异性和分布；糖尿病;2)检测IL-18和补体抑制对1型糖尿病患者细胞因子的影响；2)研究抑制IL-18和补体对胶原诱导的关节炎和类风湿滑膜细胞因子产生和疾病的影响；3)确定自身免疫性多内分泌综合征II不同临床亚型的非MHC遗传贡献。这三个基础项目将为设计未来的临床试验、监测免疫治疗的有效性和/或提供与自身免疫性疾病免疫治疗相关的替代标记物提供重要信息。

The proposed Denver Autoimmunity Center of Excellence combines the efforts of investigators with faculty appointments at the University of Colorado Health Sciences Center. Affiliated institutions include the Barbara Davis Center for Childhood Diabetes, the National Jewish Medical and Research Center, the Children's Hospital of Denver, the University Hospital of Denver, the Rocky Mountain Multiple Sclerosis Center, as well as the Denver Arthritis Clinic. Faculty have been recruited from the Departments of Immunology, Pediatrics, Medicine, Neurology, Dermatology, Pathology, and Preventative Medicine/Epidemiology, and the Human Medical Genetics Program. Within the Departments of Pediatrics and Medicine, subspecialties include endocrinology, rheumatology, clinical immunology, nephrology, pulmonary and gastroenterology. There are unique resources for clinical investigation and strong basic faculty, and in many instances a track record for combining basic and clinical investigation. The proposed Autoimmunity Center includes a strong research and clinical base in type 1 diabetes, celiac disease, systemic lupus, rheumatoid arthritis, multiple sclerosis, autoimmune skin disease, autoimmune pulmonary diseases as well as other autoimmune disorders. One unique clinical resource involves ongoing studies of newborns from both the general population and relatives of patients with type 1 diabetes who are HLA typed using cord blood and then evaluated prospectively for the development of autoantibodies associated with type 1A diabetes and disease A major strength of the current proposal we believe sit he breadth of work in Denver studying T cell recognition and biology, genetics, and the biology of inflammatory and cytokine mediators. In the current proposal, two clinical trials are proposed. Clinical Project 1 will evaluate subcutaneous insulin vaccination to prevent the appearance of anti-islet autoantibodies in infants at high risk for the development of autoantibodies and disease. Clinical Project 2 will test humanized anti-C5 mAbs in patients with active lupus nephritis. The three proposed basic components are: 1) to define the T cell specificities and distribution of insulin- and islet antigen- reactive T cells in murine models and patients with type 1; diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine patients with type1 diabetes; 2) to determine the effects of inhibition of IL-18 and complement on cytokine production and disease in collagen- induced arthritis and rheumatoid synovium; and 3) to define the non- MHC genetic contributions to different clinical subtypes of autoimmune polyendocrine syndrome II. The three basic projects will provide important information to design future clinical trials , to monitor the effectiveness of immunologic therapies, and/or provide surrogate markers to correlate with immunologic therapies in autoimmune diseases.