PEPTIDE-BASED IMMUNOMODULATION OF IDDM

基于肽的免疫疗法治疗IDDM的主要目的是 通过调节免疫平衡阻止人胰岛的破坏 抑制攻击性自身免疫这种方法将 需要选择合适的肽，优化体内 使用、适当选择佐剂和免疫途径， 最后是人体安全性和有效性试验。本项目的目标 是在实现这一目标的道路上实现其中的前两个步骤， 人类肽免疫治疗糖尿病的目标。我们将确定 来自自身抗原的肽，其适合于在糖尿病和 基因风险个体，我们将确定是否 这些肽的识别可能产生调节性的、免疫性的- 调节治疗效果。我们将分析T细胞对GAD 65的反应， 前胰岛素原和IA-2，以鉴定呈递给 在HLA-DRB 1 *0401，*0402，*0404，*0405， *0301和DQB 1 *302和 *201。在确定了关键的“短名单”之后， 肽类II配对，我们将确定特征性细胞因子 T细胞活化后的反应，并分析遗传和细胞 有助于差异抗原加工的变异， 演示文稿.详细的肽结合研究将用于调节 MHC等位基因特异性和优化和/或调节TCR识别 使用取代肽进行关键表位-II类配对。密切 与该项目中的其他项目合作，该项目将 在潜在自身抗原表位的鉴定之间架起差距， 转基因小鼠的研究和未来的基于肽的免疫治疗， 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.