Dominant CD4+ T Cell Regulation Causes Chronic Infection

CD4 T 细胞的主导调节导致慢性感染

• 批准号: 6747745
• 负责人: GRETE SONDERSTRUP
• 金额: $ 35.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6747745
• 关键词: MHC class II antigen; T cell receptor; cellular immunity; chronic disease /disorder; cytokine; epitope mapping; genetically modified animals; helper T lymphocyte; hepatitis C virus; immunogenetics; laboratory mouse; leukocyte activation /transformation; major histocompatibility complex; microorganism immunology; recombinant proteins; virus diseases; virus protein

Dominant CD4+ T Cell Regulation Causing Chronic Infection No more than 15 percent of humans who become infected with hepatitis C virus (HCV) succeed in clearing the virus achieving a complete cure; the remaining 85 percent of HCV infected humans develop chronic viral infection. Potent CD4+ T cell responses to either the HCV/NS3 or the HCV/core proteins are critical for development of virus clearing CD8+ cytotoxic T cells. Further, the HLA-DRB1 1101,DQB 0301 alleles both present on a frequent Caucasian haplotype are associated with a better prognosis and a better chance of virus clearance in HCV infected individuals. In contrast, the equally prevalent HLA-DR7, DQ2 haplotype is associated with high risk of developing chronic viral disease after infection with HCV. The proposed research will explore how these two very common HLA haplotypes handle the HCV proteins, HCV/core and NS3 antigens differently. With the hypothesis, that the HLA-DR7, DQ2 haplotype alleles are functioning with a bias for inducing regulatory T cells, which down-regulate the virus specific T helper cell responses, we propose to study TCR repertoires, cytokine responses, and peptide/MHC binding using our HLA transgenic mouse model. We will produce HLA-DRA/DRB1 1101, DQA 0501/DQB 0301 double transgenic mice and compare their HCV specific T cell responses with a similar line of HLA class II transgenic mice with the DRA/DRB1 0701, DQA 0201/DQB 0201 alleles after immunization with recombinant HCV/core or HCV/NS3 protein. These studies, including CD4+ T cell epitope mapping, development of altered peptide ligands and attempts using peptide pulsed dendritic cells or DNA/RNA plasmids for immunization, may be directly applicable in designs of new more effective HCV vaccines for humans.

占主导地位的CD 4 + T细胞调节导致慢性感染不超过15%的人感染丙型肝炎病毒（HCV）成功清除病毒，实现完全治愈;其余85%的HCV感染者发展为慢性病毒感染。 对HCV/NS 3或HCV/核心蛋白的有效CD 4 + T细胞应答对于开发清除病毒的CD 8+细胞毒性T细胞至关重要。此外，HLA-DRB 11101、DQB 0301等位基因均存在于常见的高加索人单倍型上，与HCV感染个体中更好的预后和更好的病毒清除机会相关。 相反，同样流行的HLA-DR 7，DQ 2单倍型与HCV感染后发展为慢性病毒性疾病的高风险相关。 拟议的研究将探索这两种非常常见的HLA单倍型如何不同地处理HCV蛋白、HCV/核心和NS 3抗原。假设，HLA-DR 7，DQ 2单倍型等位基因的功能与偏见诱导调节性T细胞，下调病毒特异性T辅助细胞的反应，我们建议研究TCR库，细胞因子反应，和肽/MHC结合使用我们的HLA转基因小鼠模型。 我们将制备HLA-DRB 1 1101、DQA 0501/DQB 0301双转基因小鼠，并将它们与具有HLA-DRB 1 0701、DQA 0201/DQB 0201等位基因的相似系的HLA-II转基因小鼠在用重组HCV/core或HCV/NS 3蛋白免疫后的HCV特异性T细胞应答进行比较。这些研究，包括CD 4 + T细胞表位定位，开发改变的肽配体和尝试使用肽脉冲树突状细胞或DNA/RNA质粒免疫，可能直接适用于设计新的更有效的HCV疫苗。