Lymphocyte Metabolism in Autoimmune Insulitis

项目摘要 1型糖尿病(T1D)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T1D的免疫干预是一种有吸引力的治疗方法。 一种针对糖尿病免疫反应的抗原特异性干预的开发 由于T1D抗原靶点的不断扩大，损害系统免疫的问题变得复杂起来。最近， 在自身免疫攻击部位产生的新的翻译后修饰的杂交融合多肽 胰岛也被鉴定为有效的自身抗原。因此，有效的基于抗原的治疗方法的发展 不仅需要识别抗原，还需要了解独特的抗原处理环境 是由小岛本身促成的。这项建议试图确定淋巴细胞代谢对T-B的影响 T1D中的相互作用。 低氧是T-B相互作用部位B细胞增殖和扩增的有力调节因素 初级淋巴器官的生发中心。在自身免疫期间，胰岛也会形成生发中心。 然而，低氧对胰岛生发中心的影响尚不清楚。这些生发中心是 在淋巴细胞性浸润区内形成，称为岛炎。有趣的是，并不是所有的胰岛炎损都进展到 β细胞死亡。鉴于胰岛的高度血管化性质，需要适应代谢需求 与胰岛素分泌有关，胰岛独特的代谢微环境可能会影响T 和B细胞在胰腺自身免疫攻击部位的相互作用。 这项拟议的研究将检验这样的假设，即胰岛中T-B细胞相互作用的位置是 与初级淋巴器官的代谢不同，浸润性淋巴组织的代谢特征 淋巴细胞受到不同的调节，以形成自攻性或调节性表型，这些表型要么驱动要么 防止T1D的发展。在目标1中，我们将评估胰岛的新陈代谢环境 随着糖尿病的进展，影响免疫效应器的反应。一种独特的低氧探头将用于评估 胰岛氧分压的变化及代谢表型和实时生物能量分析的结合 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， 转基因NOD小鼠模型将被用来描述区分无害的代谢参数 是由破坏性的岛炎引起的。这些研究将确定自身免疫的特征代谢特征和 T1D的耐受性--这些差异可能被用于未来的治疗干预。

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.