Treatment/Type 1 Diabetes/hGAD65 Altered Peptide Ligand

描述(由申请人提供)： 关键的免疫学和临床安全性问题将直接与人类T细胞克隆的体外分析和小鼠模型的体内研究相结合进行评估。在这项应用的第一阶段(R21)，APL特异性、敏感性和多克隆T细胞活性的里程碑将通过结构和机械方法来解决。在人类白细胞抗原-DR4转基因小鼠中，将严格评估与天然hGAD65的抗原交叉反应，以达到进入该项目第二阶段(R33)的里程碑。在成功完成这些里程碑后，我们建议为患者的I期研究提交IND和临床试验方案。这一阶段应用的安全标准包括免疫学、代谢和神经学结果。新的人类白细胞抗原-GAD四聚体分析将被用来评估在治疗APL期间抗原特异性的CD4+T细胞的免疫紊乱。这项研究计划将G.Nepom博士的免疫学实验室的专业知识与C.Greenbaum博士的临床研究专业知识结合起来，建立合作伙伴关系，对潜在的新糖尿病疗法进行全面评估。VMRC的这个由基础和临床科学家组成的团队每周举行联合会议，非常适合迅速从可行性研究转移到开发和临床试验。

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.