PEPTIDE-BASED IMMUNOMODULATION OF IDDM

IDDM多肽免疫治疗的主要目的是 通过调节免疫平衡阻止人类胰岛的破坏 降低侵袭性自身免疫力。这一方法将 需要选择合适的多肽，进行体内优化 使用、适当选择佐剂和免疫途径以及 最后，人体安全性和有效性试验。这个项目的目标是 是实现这些步骤中的前两个步骤 人类多肽免疫治疗糖尿病的目标。我们将确定 适合糖尿病和糖尿病患者识别的自身抗原多肽 基因高危个体，我们将确定 对这些多肽的识别可能会产生调节、免疫- 可调节的治疗结果。我们将分析T细胞对GAD65的反应， 前胰岛素原和IA-2用于鉴定呈现给 人类CD4+T细胞在人类白细胞抗原-DRB1*0401，*0402，*0404，*0405， *0301，以及DQB1*302和*201。在确定关键字的“短名单”之后 多肽-II类配对，我们将确定特征细胞因子 T细胞激活后的反应并分析遗传和细胞 有助于差异抗原处理的变异和 演示文稿。将使用详细的多肽结合研究来调节 MHC等位基因特异性以及优化和/或调节TCR识别 使用取代多肽进行关键的表位II类配对。近距离 与该计划中的其他项目协作，该项目将 弥合潜在自身抗原表位鉴定之间的差距 转基因小鼠的研究和未来基于多肽的免疫治疗 人类。

The principal objective of peptide-based immunotherapy in IDDM is to arrest human islet destruction by modulating the immunologic balance towards down-regulation of aggressive autoimmunity. This approach will require selection of the appropriate peptides, optimization for in vivo use, appropriate choices of adjuvants and route of immunization and finally, human safety and efficacy trials. The objective of this project is to achieve the first two of these steps on the path to realizing the goal of human peptide immunotherapy for diabetes. We will identify the peptides from autoantigens suitable for recognition in diabetic and genetically at-risk individuals and we will determine whether the recognition of these peptides is likely to yield regulatory, immune- modulatory therapeutic outcome. We will analyze T cell responses to GAD65, pre pro-insulin, and IA-2 to identify immunodominant peptides presented to human CD4+ T cells in the context of HLA-DRB1*0401, *0402, *0404, *0405, *0301, and DQB1*302 and *201. After determining a "short list" of key peptide-class II pairings, we will determine characteristic cytokine responses following T cell activation and analyze genetic and cellular variation which contributes to differential antigen processing and presentation. Detailed peptide binding studies will be used to modulate both MHC allelic specificity and optimize and/or modulate TCR recognition using substituted peptides for key epitope-class II pairings. In close collaboration with the other projects in this program, this project will bridge the gap between identification of potential autoantigen epitopes in the transgenic mouse studies and future peptide based immunotherapy in humans.