Innate and Adaptive Immune Responses in Pre-type 1 Diabetes

描述（由申请人提供）：导致1型糖尿病（T1DM）发展的免疫事件尚未明确定义。了解导致β细胞破坏的免疫事件是机制研究的一个重要目标，因为它们可能提出合理的治疗方法。先天性和适应性免疫反应都被认为参与了糖尿病的发生和传播。我们的研究小组之前已经发现了循环单核细胞的异常，以及1型糖尿病患者I类MHC四聚体中自身反应性CD8+ T细胞的频率增加。在这个提议中，我们计划通过研究TrialNet自然历史研究（NHS）收集的外周血中的这些细胞来确定在T1DM诊断之前是否存在先天和/或适应性免疫异常。我们要求NHS HLA-A2+参与者外周血单个核细胞样本。我们将确定自身抗体+亲属是否有这些异常，以及它们是否预测β细胞衰竭的进展。在亚研究分析中，我们还将比较先天和适应性异常的时间，以便确定疾病的免疫进展。拟议的研究涉及到博士的实验室之间的合作。大卫·哈弗勒和凯文·赫罗德。这样安排是为了确保NHS研究的有效利用，并避免解冻细胞的浪费——两位研究者将对来自同一样本的不同细胞群进行分析。将获得的数据：炎症介质基因的相对表达和CD8+ T细胞的百分比和定性测量，将与TNCC合作分析，并与临床和其他免疫学参数相关。

DESCRIPTION (provided by applicant): The immunologic events that lead to the development of Type 1 diabetes mellitus (T1DM) are not clearly defined. Understanding the immunologic events that lead to beta cell destruction is an important goal of mechanistic studies since they are likely to suggest rational treatment approaches. Both innate and adaptive immune responses are thought to be involved in the initiation and propagation of diabetes. Our group has previously identified abnormalities in circulating monocytes as well as an increased frequency of autoreactive CD8+ T cells in patients with Type 1 diabetes with Class I MHC tetramers. In this proposal, we plan to determine whether innate and/or adaptive immune abnormalities are present before the diagnosis of T1DM by studying these cells in peripheral blood collections from the TrialNet Natural History Study (NHS). We are requesting peripheral blood mononuclear cell samples from HLA-A2+ participants in the NHS. We will determine whether autoantibody+ relatives do or do not have these abnormalities and whether they predict progression of beta cell failure. In a substudy analysis, we will also compare the timing of innate and adaptive abnormalities so that the immunologic progression of the disease can be identified. The proposed studies involve a collaboration between the laboratories of Drs. David Hafler and Kevan Herold. This arrangement was made to ensure an efficient use of the NHS studies and to avoid waste of thawed cells - both investigators will carry out analyses on separate cell populations derived from the same sample. The data that will be obtained: relative expression of genes of inflammatory mediators and percentage and qualitative measures of CD8+ T cells, will be analyzed in collaboration with the TNCC and correlated with clinical and other immunologic parameters. PUBLIC HEALTH RELEVANCE: This proposal is to carry out analyses of innate and adaptive immune responses in participants in the TrialNet Natural History Study. We are requesting samples from autoantibody relatives of patients who do and do not progress to diabetes.