IMMUNE RESPONSE IN INSULIN-DEPENDENT DIABETES

这项修订建议的目的是确定免疫反应 对自身免疫的发展很重要的机制， 胰腺β细胞 我们对常态的理解有了重大突破 人类免疫应答与HLA分子遗传学 分子及其在抗原呈递、分子克隆和 T细胞受体的表征， 免疫球蛋白基因和抗体形成的控制，以及 鉴定大量细胞因子和淋巴因子， 生物功能。 采取协调的多学科方法， 考虑到免疫反应的这些不同的关键功能， 为了了解自身免疫反应， 负责胰腺β细胞的特异性根除， 胰岛素依赖型糖尿病 在这个项目中，我们将测试胰腺β蛋白的丢失是否 细胞依赖于相互作用的免疫机制的模式。 具体来说，我们将阐明这种疾病是否涉及异常 1）β细胞抗原生物合成和/或表达以及 胰岛素促分泌素和炎症介质; 2）加工和MHC- β细胞抗原的限制性呈递; 3） 特异性T细胞应答，其特征在于T细胞的限制性使用 受体基因; 4）通过限制使用 免疫球蛋白基因和5）炎性细胞的体内控制 胰岛内和周围的反应性。 的病理生理 这些遗传和免疫标记的意义将在共享的 患者和对照群体以及转基因小鼠或实验小鼠中 动物

The objective of this revised proposal is to identify immune response mechanisms which are important to the development of autoimmunity against the pancreatic beta cells. There have been major breakthroughs in our understanding of the normal human immune response with respect to the molecular genetics of HLA molecules and their role in antigen presentation, molecular cloning and characterization of the T-cell receptor, the molecular genetics of immunoglobin genes and the control of antibody formation, as well as the identification of a large number of cyto- and lymphokines with multiple biological functions. A coordinated mulltidisciplinary approach taking into account these different key functions of the immune response is yet to be carried out in order to understand the autoimmune response which may be responsible for the specific eradication of the pancreatic beta cells in insulin-dependent diabetes. In this program project we shall test whether the loss of pancreatic beta cells is dependent on a pattern of interacting immunologic mechanisms. Specifically, we will elucidate whether this disease involves abnormalities in 1) beta cell antigen biosynthesis and/or expression and the effects of insulin secretagogues and inflammatory mediators; 2) processing and MHC- restricted presentation of beta cell antigens; 3) the activation of specific T cell responses characterized by a restricted use of T cell receptor genes; 4) the formation of autoantibodies by a restricted use of immunoglobulin genes and 5) the in vivo control of the inflammatory cell reactivity in and around the pancreatic islets. The pathophysiologic significance of these genetic and immune markers will be tested in shared patient and control populations and in transgenic mice or experimental animals.