Discovery and Treatment of the Early Autoimmune Reaction In Type 1 Diabetes

1 型糖尿病早期自身免疫反应的发现和治疗

• 批准号: 8240614
• 负责人: Thomas J. Kodadek
• 金额: $ 502.92万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240614
• 关键词: Address; Affect; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Automobile Driving; B-Lymphocytes; Binding Sites; Biological Markers; Blood; Blood Tests; Bypass; Clinical; Detection; Development; Diabetes Mellitus; Diabetes autoantibodies; Diagnosis; Diagnostic tests; Disease; Disease Management; Early treatment; Evaluation; Evolution; Goals; Human; Immune system; Immunosuppression; In Vitro; Inbred NOD Mice; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Lead; Ligands; Methodology; Molecular; Mus; Natural History; Patients; Peptoids; Pharmaceutical Preparations; Plant Roots; Population; Reaction; Recording of previous events; Relative (related person); Screening procedure; Staging; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Time; antigen binding; autoreactive B cell; autoreactive T cell; base; cohort; early onset; innovation; insight; mouse model; new technology; novel; novel marker; novel therapeutics; reconstruction; research study; response; small molecule libraries

DESCRIPTION (provided by applicant): The goal of this project is to identify and characterize the earliest autoreactive T cells and antibodies in type I diabetes, both in the NOD mouse model and in humans. This will be done using a novel chemical library screening-based technology recently developed in the laboratory of the P.I. It facilitates an unbiased search for antigen-specific antibodies or T cells that are highly elevated in the blood of patients with a particular disease, but are essentially absent in matched controls. No knowledge of the antigens recognized by the antibodies or T cells is required. This effort will address several unmet critical needs in the field. For example, we will develop a simple blood test for early onset, and hopefully pre-symptomatic, type I diabetes. This would have a profound impact on the management of this disease. We will also construct a complete "history" of the different antigen-specific autoimmune reactivities that arise in the NOD mouse over time. This should contribute a great deal of fundamental knowledge regarding the molecular mechanism of disease development in the mouse and perhaps in humans as well.. Finally, we will evaluate a novel therapeutic strategy in which the activities of the autoimmune B and T cells are blocked using synthetic compounds that target the antigen- binding sites of autoantibodies and autoreactive T cell receptors. This effort will point the way to a revolutionary approach to the treatment of type I diabetes, and autoimmune diseases in general, in which the root cause of the disease is treated without the need for general immunosuppression. Thus, we believe that the successful completion of this project will have a major impact on the diagnosis, treatment and understanding of type I diabetes. PUBLIC HEALTH RELEVANCE: This project aims to identify novel antibodies and T cells involved in the progression of type I diabetes. We hope that this will lead to effective diagnostic tests for early stage disease and also set the stage for a novel therapeutic strategy in which only the autoimmune components of the immune system are targeted.

描述（由申请人提供）：该项目的目的是识别和表征I型糖尿病中最早的自动反应性T细胞和抗体，无论是在NOD小鼠模型还是在人类中。这将使用最近在P.I.实验室开发的新型化学库筛选技术来完成。它促进了对特定疾病患者血液中高度升高的抗原特异性抗体或T细胞的公正搜索，但在匹配的对照中基本上不存在。不需要抗体或T细胞识别的抗原。这项工作将解决该领域的几个未满足的关键需求。例如，我们将对早期发作和希望症状的I型糖尿病进行简单的血液检查。这将对这种疾病的管理产生深远的影响。我们还将构建一个随着时间的流逝而在NOD小鼠中产生的不同抗原特异性自身免疫反应率的完整“历史”。这应该对小鼠以及人类疾病发展的分子机制有很多基本知识。这项努力将指向革命性的I型糖尿病的方法，以及一般而言的自身免疫性疾病，在这种方法中，该疾病的根本原因无需一般的免疫抑制。因此，我们认为该项目的成功完成将对I型糖尿病的诊断，治疗和理解产生重大影响。 公共卫生相关性：该项目旨在确定与I型糖尿病进展有关的新型抗体和T细胞。我们希望这将导致早期疾病的有效诊断测试，并为一种新型的治疗策略奠定了基础，在这种策略中，只有免疫系统的自身免疫成分才是针对的。