Targeting CD8+ T Cells to Prevent b Cell Destruction

1型糖尿病(T1-D)是一种组织特异性自身免疫性疾病，其特征是T细胞介导的 朗格汉斯胰岛分泌胰岛素的b细胞的破坏。对糖尿病的治疗有 重点介绍了胰岛素替代疗法的使用情况。然而，这种治疗方法可能很难规范和 有很多缺点。虽然移植胰岛的外科技术现在处于 另一方面，问题依然存在。首先也是最重要的事实是，即使是同基因移植物也会被排斥 与最初导致胰岛细胞丢失的自身免疫机制相同。这一过程必须是 控制以促进有效的移植功能。到目前为止，大多数在理解方面的努力 T1D的发病机制和治疗主要集中在CD4+T细胞的作用上。在本建议书中 我们将目前的免疫调节思想扩展到T1D的CD8+细胞。我们试图研究 B细胞特异性CD8+T细胞的谱系和调节，CD8+T细胞亚群的作用，TCL和 Tc2对CD8+T细胞的调节作用及CD8+T细胞产生的细胞因子对CD8+T细胞的影响 回应。这将通过结合使用MHC I类四聚体、多肽和 新的免疫策略。然后，我们将使用此信息来偏离或确认/删除 多肽特异性T细胞和控制T1D中关键的CD8+T细胞反应以允许有效的胰岛 细胞移植。

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 syngeneic 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 anergize/delete peptide specific T cells and control the critical CD8+ T cell response in T1D to allow effective islet cell transplantation.