IMMUNE RESPONSE IN INSULIN-DEPENDENT DIABETES

这项修订提案的目的是识别免疫反应 对自身免疫的发展至关重要的机制 胰岛β细胞。 我们对常态的理解已经有了重大突破 人类免疫反应与人类白细胞抗原分子遗传学的关系 分子及其在抗原提呈、分子克隆和免疫反应中的作用 T细胞受体的特性，分子遗传学 免疫球蛋白基因与抗体形成的控制，以及 大量细胞因子和淋巴因子的鉴定 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 以了解自身免疫反应，这可能是 负责特定的根除胰腺中的β细胞 胰岛素依赖型糖尿病。 在这个计划项目中，我们将测试胰岛β细胞的丢失 细胞依赖于一种相互作用的免疫机制模式。 具体地说，我们将澄清这种疾病是否涉及异常 在1)β细胞抗原的生物合成和/或表达以及 胰岛素促分泌剂和炎症介质；2)加工和MHC- 限制β细胞抗原的提呈；3)激活 以限制使用T细胞为特征的特异性T细胞反应 受体基因；4)自身抗体的形成通过限制使用 免疫球蛋白基因和5)炎症细胞的体内调控 胰岛及其周围的反应性。病理生理学 这些遗传和免疫标记的重要性将在Shared 患者和对照人群以及转基因小鼠或实验性小鼠 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.