Treatment/Type 1 Diabetes/hGAD65 Altered Peptide Ligand

治疗/1 型糖尿病/hGAD65 改变的肽配体

• 批准号: 6575447
• 负责人: GERALD T NEPOM
• 金额: $ 42万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575447
• 关键词: T cell receptor; T lymphocyte; autoantigens; cell proliferation; cellular immunity; clinical research; cross immunity; diabetes mellitus therapy; gene expression; genetically modified animals; glutamate decarboxylase; helper T lymphocyte; histocompatibility antigens; human subject; human therapy evaluation; immunomodulators; immunotherapy; insulin; insulin dependent diabetes mellitus; laboratory mouse; ligands; mass spectrometry; pancreatic islets; patient oriented research; peptides

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.

描述（由申请人提供）： 关键的免疫学和临床安全问题将与人类 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直接评估。在该应用的第一阶段 (R21)，将通过结构和机制方法解决 APL 特异性、敏感性和多克隆 T 细胞活性的里程碑。将在 HLA-DR4 转基因小鼠中严格评估与天然 hGAD65 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。成功完成这些里程碑后，我们建议提交 IND 和临床试验方案，以进行患者的 I 期研究。此阶段应用的安全标准包括免疫、代谢和神经系统结果。新型 HLA-GAD 四聚体检测将用于评估 APL 治疗期间抗原特异性 CD4+ T 细胞的免疫扰动。该研究计划将 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相结合，建立合作伙伴关系，对潜在的新型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一次联合会议，非常适合快速从可行性研究转向开发和临床试验。