MODULATION OF EFFECTOR T CELLS IN DIABETES

1型糖尿病代表了对β细胞抗原特异性的CD4+和CD8+ T细胞选择致病机制而不是零耐受性的破坏性决定的最终结果。该计划项目资助汇集了三位研究者，他们已经建立了一个持续的合作关系，目的是了解这一决定的基础，并确定可以预防这种自身免疫的免疫疗法。在项目1中，Webb博士将确定初始CD4+细胞被激活的初始条件如何最终影响它们在体内的迁移和致病特性。拟议的研究将确定有助于这些决定的调节分子。中和抗体和细胞因子/趋化因子缺陷小鼠将被用来识别触发胰腺炎症的分子。在项目2中，Sherman博士专注于诱导对胰岛中表达的自身抗原具有低亲和力的CD8+ T细胞成为致病性的途径。待测试的潜在致病性外部调节剂包括强激活的改变肽配体、差异激活的CD4细胞、病毒感染和一般促炎环境的影响。在项目3中，Sarvetnick博士将使用在其胰岛中表达个体细胞因子的NOD小鼠来测试CD8+细胞被激活的细胞因子环境通过影响其寿命来改变其致病潜力的假设。还将验证1型和2型细胞因子对CD8+细胞的作用与对CD4+细胞的作用相反，即2型细胞因子促进疾病的假设。博士们的合作目标。Sherman和Sarvetnick将确定GAD DNA疫苗诱导的糖尿病保护机制。初步实验表明，预防可能通过CD8 T细胞耐受发生。

Type 1 diabetes represents the end result of a devastating decision on the part of CD4+ and CD8+ T cells specific for beta cell antigens to chose pathogenesis rather than zero tolerance. This Program Project grant brings together three investigators that have established an on-going collaboration with the goal of understanding the basis for this decision, and identifying immunotherapies that will prevent such autoimmunity. In Project 1, Dr. Webb will determine how the initial conditions which naive CD4+ cells become activated ultimately influence their migration and pathogenic properties in vivo.. The proposed studies will define the regulatory molecules that contribute to these decisions. Neutralizing antibodies and cytokine/chemokine deficient mice will be used to identify molecules that trigger inflammation in the pancreas. In Project 2, Dr. Sherman focuses on pathways that induce CD8+ T cells that have low affinity for a self-antigen expressed in the islets to become pathogenic. Potential external modulators of pathogenicity to be tested include strongly activating altered peptide ligands, the presence of differentially activated CD4 cells, viral infection, and the influence of a generally pro- inflammatory milieu. In Project 3, Dr. Sarvetnick will use NOD mice expressing individual cytokines in their islets to test the hypothesis that the cytokine milieu in which CD8+ cells are activated alter their pathogenic potential by affecting their longevity. The hypothesis will also be tested that the effect of type 1 and type 2 cytokines on CD8+ cells is opposite to that on CD4+ cells, such that type 2 cytokines promote disease. A collaborative goal of Drs. Sherman and Sarvetnick is to define the mechanism of protection from diabetes as induced by a GAD DNA vaccine. Preliminary experiments suggest prevention may occur through CD8 T cell tolerance.