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

描述（由申请人提供）：该项目的目标是在NOD小鼠模型和人类中识别和表征I型糖尿病中最早的自身反应性T细胞和抗体。这将使用P.I.实验室最近开发的一种新的基于化学文库筛选的技术来完成，它有助于无偏倚地搜索抗原特异性抗体或T细胞，这些抗体或T细胞在患有特定疾病的患者血液中高度升高，但在匹配的对照中基本不存在。不需要知道抗体或T细胞识别的抗原。这一努力将解决该领域若干未得到满足的关键需求。例如，我们将开发一种简单的血液测试，用于早期发病，希望是症状前的I型糖尿病。这将对这种疾病的管理产生深远的影响。我们还将构建不同抗原特异性自身免疫反应的完整“历史”，这些反应随着时间的推移在NOD小鼠中出现。这应该有助于大量的基本知识，关于疾病发展的分子机制，在小鼠和人类也许也是如此。最后，我们将评估一种新的治疗策略，在这种策略中，使用针对自身抗体和自身反应性T细胞受体的抗原结合位点的合成化合物来阻断自身免疫B细胞和T细胞的活性。这一努力将为I型糖尿病和一般自身免疫性疾病的治疗指明一条革命性的方法，在这种方法中，疾病的根本原因不需要一般的免疫抑制就能得到治疗。因此，我们相信该项目的成功完成将对I型糖尿病的诊断、治疗和认识产生重大影响。

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.