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

基本信息

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
项目类别：
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

项目摘要

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）：该项目的目标是在 NOD 小鼠模型和人类中鉴定和表征 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. 实验室最近开发的基于化学库筛选的新型技术来完成。它有助于公正地寻找抗原特异性抗体或 T 细胞，这些抗体或 T 细胞在患有特定疾病的患者的血液中高度升高，但在匹配的对照中基本上不存在。不需要了解抗体或 T 细胞识别的抗原。这项工作将解决该领域一些未满足的关键需求。例如，我们将开发一种简单的血液测试来检测早发的 I 型糖尿病，希望是出现症状前的 I 型糖尿病。这将对这种疾病的治疗产生深远的影响。我们还将构建 NOD 小鼠随时间推移出现的不同抗原特异性自身免疫反应的完整“历史”。这应该有助于提供关于小鼠甚至人类疾病发展的分子机制的大量基础知识。最后，我们将评估一种新的治疗策略，其中使用阻断自身免疫 B 和 T 细胞的活性靶向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。这项工作将为治疗 I 型糖尿病和一般自身免疫性疾病指明道路，其中无需一般免疫抑制即可治疗疾病的根本原因。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。公共健康相关性：该项目旨在识别参与 I 型糖尿病进展的新型抗体和 T 细胞。我们希望这将为早期疾病带来有效的诊断测试，并为一种仅针对免疫系统自身免疫成分的新型治疗策略奠定基础。