MODULATION OF EFFECTOR T CELLS IN DIABETES

1型糖尿病代表了一个毁灭性的决定的最终结果，即部分针对β细胞抗原的CD4+和CD8+T细胞选择了发病机制，而不是零耐受。这项计划项目赠款将三名研究人员聚集在一起，他们建立了持续的合作，目的是了解这一决定的基础，并确定将防止这种自身免疫的免疫疗法。在项目1中，韦伯博士将确定初始状态下被激活的CD4+细胞最终如何影响它们在体内的迁移和致病特性。拟议的研究将定义对这些决定起作用的调控分子。中和抗体和细胞因子/趋化因子缺陷小鼠将被用来识别引发胰腺炎症的分子。在项目2中，Sherman博士专注于诱导CD8+T细胞致病的途径，CD8+T细胞对胰岛中表达的自身抗原具有低亲和力。待测试的潜在致病性外部调节因素包括强烈激活改变的多肽配体、差异激活的CD4细胞的存在、病毒感染以及一般促炎环境的影响。在项目3中，Sarvetnick博士将使用在胰岛表达单个细胞因子的NOD小鼠来检验这样一个假设，即CD8+细胞被激活的细胞因子环境通过影响它们的寿命来改变它们的致病潜力。这一假设还将被检验，即1型和2型细胞因子对CD8+细胞的影响与对CD4+细胞的作用相反，因此2型细胞因子促进疾病。Sherman博士和Sarvetnick博士的合作目标是定义GAD DNA疫苗诱导的预防糖尿病的机制。初步实验表明，可以通过CD8 T细胞耐受来预防。

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.