Targeting CD8+ T Cells to Prevent b Cell Destruction

描述（由申请人提供）：1型糖尿病（T1 D）是一种组织特异性自身免疫性疾病，其特征在于T介导的胰岛的胰岛素产生B细胞的破坏。糖尿病的治疗主要集中在使用胰岛素替代。然而，这种治疗可能难以规范，并且有许多缺点。虽然胰岛移植的外科技术现在已经掌握，但问题仍然存在。首先也是最重要的是，即使是雌激素性移植物也会由于引起最初胰岛细胞损失的相同自身免疫机制而被排斥。这个过程必须加以控制，以促进有效的移植功能。因此，在理解T1 D的发病机制和治疗方面的大部分努力都集中在CD 4 + T细胞的作用上。在这个建议中，我们扩展了目前的想法免疫调节CD 8+细胞在T1 D。我们试图研究B细胞特异性CD 8 + T细胞的库和调节，CD 8 + T细胞亚群、Tcl和Tc 2在调节中的作用，以及由CD 4 + T细胞产生的细胞因子在形成CD 8 + T细胞应答中的作用。这将通过结合使用MHC I类四聚体、肽和新的免疫策略来实现。然后，我们将使用这些信息来偏离或激活/删除肽特异性T细胞，并控制T1 D中关键的CD 8 + T细胞应答，以允许有效的胰岛细胞移植。

DESCRIPTION (provided by the applicant): Type 1 diabetes (T1 D) is a tissue specific autoimmune disease characterized by the T mediated destruction of the insulin producing b cells of the islets of Langerhans. Treatment of diabetes has focused on the use of insulin replacement. However, this treatment can be difficult to regulate and has many shortcomings. While the surgical techniques for transplanting pancreatic islets is now at hand, problems remain. First and foremost is that fact that even gynogenic grafts are rejected due to the same autoimmune mechanisms that caused the initial islet cell loss. This process must be controlled to promote effective transplant function. Heretofore, most of the efforts in understanding the pathogenesis and treatment of T1D have focused on the role of CD4+ T cells. In this proposal we expand the current ideas of immunoregulation to CD8+ cells in T1D. We seek to study the repertoire and regulation of b cell specific CD8+ T cells, the role of CD8+ T cell subset, Tcl and Tc2 on regulation, and the roles of cytokines produced by CD4+ T cells in shaping the CD8+ T cell response. This will be accomplished by combing the use of MHC class I tetramers, peptides and novel immunization strategies. We will then use this information to deviate or energize/delete peptide specific T cells and control the critical CD8+ T cell response in T1D to allow effective islet cell transplantation.