Lymphocyte Metabolism in Autoimmune Insulitis

项目摘要 1型糖尿病（T1 D）导致免疫介导的胰岛素产生β细胞的破坏， 胰腺因此，预防、延迟或逆转T1 D的免疫干预是一种有吸引力的治疗方法。 开发靶向致糖尿病免疫应答的抗原特异性干预， 由于T1 D中抗原性靶点的扩展列表，损害全身免疫性变得复杂。最近， 本发明提供了一种新的、在免疫后修饰的杂合融合肽， 胰岛也被鉴定为有效自身抗原。因此，开发有效的基于抗原的治疗方法， 不仅需要抗原鉴定，还需要了解独特的抗原处理环境， 是由小岛本身促成的该提案旨在确定淋巴细胞代谢对T-B的影响， 在T1 D中的相互作用 缺氧是一种有效的调节B细胞增殖和扩增的位点上的T-B相互作用， 初级淋巴器官的生殖中心。在自身免疫过程中， 然而，缺氧对胰岛生长中心的影响尚不清楚。这些老人中心是 在淋巴细胞浸润区域内形成，称为胰岛炎。有趣的是，并非所有的胰岛炎病变进展到 β细胞死亡鉴于胰岛需要高度血管化的性质来适应代谢需求 与胰岛素分泌相关，胰岛独特的代谢微环境可能影响T 和B细胞在胰腺自身免疫攻击部位的相互作用。 这项拟议中的研究将检验胰岛中T-B细胞相互作用的位点是 与初级淋巴器官的代谢不同，浸润性淋巴细胞的代谢特征 淋巴细胞被差异调节以发展自身攻击性或调节性表型， 预防T1 D的发展。在目标1中，我们将评估胰岛中的代谢环境如何 随着糖尿病的发展，影响免疫效应反应。将使用一种独特的缺氧探针来评估 胰岛氧分压的变化以及代谢表型和实时生物能量的组合 分析将用于确定整个疾病过程中细胞能量来源的变化。在目标2中， 将使用转基因NOD小鼠模型来描绘区分无害的代谢参数。 破坏性胰岛炎这些研究将确定自身免疫的特征性代谢特征， T1 D的耐受性--可能用于未来治疗干预的差异。

Project Summary Type 1 diabetes (T1D) results in the immune-mediated destruction of insulin-producing beta cells in the pancreas. As such, immune intervention to prevent, delay, or reverse T1D is an appealing therapeutic approach. Development of an antigen-specific intervention that targets the diabetogenic immune response without compromising systemic immunity is complicated by an expanding list of antigenic targets in T1D. Recently, novel, post-translationally modified hybrid fusion peptides generated at the site of autoimmune attack in the islet have also been identified as potent autoantigens. Thus, development of effective antigen-based therapy requires not only antigen identification, but also an understanding the unique antigen processing environment facilitated by the islet itself. This proposal seeks to identify the effects of lymphocyte metabolism on T-B interactions in T1D. Hypoxia is a potent regulator of B cell proliferation and expansion at the site of T-B interactions in the germinal center of primary lymphoid organs. Germinal centers also form in the islets during autoimmune attack; however, the effect of hypoxia on islet germinal centers is not known. These germinal centers are formed within areas of lymphocytic infiltrate, termed insulitis. Interestingly, not all insulitis lesions progress to beta cell death. Given the highly vascularized nature of the islet needed to accommodate the metabolic demand associated with insulin secretion, it is possible that the islet’s distinct metabolic microenvironment influences T and B cell interactions at the site of autoimmune attack in the pancreas. The proposed research will test the hypothesis that the sites of T-B cell interactions in the islet are metabolically distinct from those of primary lymphoid organs and that the metabolic profiles of infiltrating lymphocytes are differentially regulated to develop autoaggressive or regulatory phenotypes that either drive or protect against the development of T1D. In aim 1, we will assess how the metabolic environment in the islet shapes the immune effector response as diabetes progresses. A unique hypoxia probe will be used to assess changes in islet oxygen tension and a combination of metabolic phenotyping and real-time bioenergetic analysis will be used to identify changes in cellular energy sources throughout the disease process. In aim 2, transgenic NOD mouse models will be used to delineate the metabolic parameters that distinguish innocuous from destructive insulitis. These studies will identify characteristic metabolic features of autoimmunity and tolerance in T1D -- differences that may be harnessed for future therapeutic interventions.