T Follicular Helper Cells and Type 1 Diabetes

描述（由申请人提供）：IA型或胰岛素依赖型糖尿病（T1D）是由自身免疫过程破坏胰岛中产生胰岛素的β细胞引起的。临床试验表明，靶向适应性免疫系统可以保持细胞功能，但对T1D进行干预的主要障碍是对该疾病关键早期阶段的干预有限。该项目的目的是验证一种新的CD4+ T细胞亚群，T滤泡辅助细胞（TFH）作为T1D耐受破坏的关键早期介质的地位。疫苗生物学的最新进展表明，高亲和力的IgG抗体需要TFH的作用。因此，我们认为T1D中的高亲和力自身抗体反映了TFH在疾病早期关键检查点的作用。为了研究TFH在NOD小鼠T1D进展中的分化和功能，我们建立了一个新的模型，使用靶向（敲入）抗胰岛素VH基因检测TFH驱动的类开关重组（IgG）在T1D中的作用。该模型将在Specific Aims中进行测试，1)确定TFH在T1D中启动免疫耐受丧失的位点和阶段，2)确定调节性T细胞对T1D中TFH发生的贡献。该模型将验证T1D进展中的一个新的早期检查点，并将为未来的早期诊断和干预提供更好的靶点。

DESCRIPTION (provided by applicant): Type IA or insulin dependent diabetes (T1D) results from of an autoimmune process that destroys insulin producing beta cells in the pancreatic islets. Clinical trials demonstrate that targeting the adaptive immune system can preserve 2 cell function, but a major road block to intervention in T1D is limited access to critical early stages of the disorder. The goal of this project is to validate the position of a novel CD4+ T cell subset, T follicular helper cells (TFH) as critical early mediators of the breach of tolerance in T1D. Recent advances in vaccine biology reveal that high affinity IgG antibodies require the action of TFH. Accordingly, we propose the high affinity autoantibodies in T1D reflect the actions of TFH at a critical early checkpoint in the disease. To investigate TFH differentiation and function in the progression of T1D in NOD mice, we developed a new model that uses a targeted (knock-in) anti-insulin VH gene to detect TFH driven class switch recombination (IgG) in T1D. This model will be tested in Specific Aims that 1) identify the sites and stages in T1D when TFH initiate loss of immune tolerance, and 2) determine the contribution of regulatory T cells to the genesis of TFH in T1D. The model will validate a new early checkpoint in T1D progression and will provide better targets for early diagnosis and intervention in the future. . PUBLIC HEALTH RELEVANCE: Over the past decade the incidence of T1D has increased at an alarming rate of 3% per year in a world-wide distribution and in multiple ethnic groups. Despite improved metabolic control with insulin delivery systems, T1D remains a major cause of renal failure, blindness, amputations, and cardiovascular disease. This project offers the prospect to identify a previously unrecognized target for diagnosis and therapy.