Treatment/Type 1 Diabetes/hGAD65 Altered Peptide Ligand

描述（由申请人提供）： 关键免疫学和临床安全性问题将与人T细胞克隆的体外分析和鼠模型中的体内研究一起直接评价。在本申请的第一阶段（R21），APL特异性、敏感性和对多克隆T细胞的活性的里程碑将通过结构和机制方法来解决。将在HLA-DR 4转基因小鼠中严格评估与天然hGAD 65的抗原交叉反应性，以满足推进该项目第二阶段（R33）的里程碑。在成功完成这些里程碑后，我们建议提交IND和临床试验方案，用于患者的I期研究。该阶段应用的安全性标准包括免疫学、代谢和神经学结局。新型HLA-GAD四聚体测定将用于评估治疗性APL给药期间抗原特异性CD 4 + T细胞的免疫扰动。这项研究计划结合了G. Nepom的免疫学实验室拥有C. Greenbaum在一个合作伙伴关系，全面评估一个潜在的新的糖尿病治疗。VMRC的基础和临床科学家团队每周举行联席会议，非常适合快速从可行性研究转向开发和临床试验。

DESCRIPTION (provided by applicant): Key immunologic and clinical safety issues will be directly evaluated in concert with in vitro analysis of human T cell clones and in vivo studies in a murine model. In the first phase (R21) of this application, milestones for APL specificity, sensitivity, and activity on polyclonal T cells will be addressed by both structural and mechanistic approaches. Antigenic cross-reactivity with native hGAD65 will be rigorously evaluated in HLA-DR4 transgenic mice to meet milestones for advancing to the second phase (R33) of this project. After successful completion of these milestones, we propose to submit an IND and clinical trial protocol for a phase I study in patients. Safety criteria for this phase of the application include immunologic, metabolic, and neurologic outcomes. Novel HLA-GAD tetramer assays will be used to evaluate immunologic perturbations of antigen-specific CD4+ T cells during therapeutic APL administration. This research plan combines the expertise of Dr. G. Nepom's immunology laboratory with the clinical research expertise of Dr. C. Greenbaum in a collaborative partnership for comprehensive evaluation of a potential new diabetes therapy. This team of basic and clinical scientists at VMRC holds joint weekly meetings and is well suited to expeditiously move from feasibility studies to development and clinical trials.