Novel targets for vaccines against tuberculosis

结核病疫苗的新靶标

• 批准号: 6859051
• 负责人: YURI BUSHKIN
• 金额: $ 23.34万
• 依托单位: PUBLIC HEALTH RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859051
• 关键词: Mycobacterium; alanine; bacterial proteins; cellular immunity; cytotoxic T lymphocyte; flow cytometry; genetically modified animals; glutamate ammonia ligase; immune response; laboratory mouse; oxidoreductase; polymerase chain reaction; technology /technique development; tuberculosis; vector vaccine

DESCRIPTION (provided by applicant): We have obtained evidence that in humans the profile of antigen-specific immune responses associated with active disease differs from that observed with latent infection. HLA-A2-restricted, Th1-type cytotoxic T lymphocyte responses against mycobacterial alanine dehydrogenase and glutamine synthetase can be detected only in non-vaccinated, tuberculin skin test-positive asymptomatic individuals but not in active tuberculosis patients. In the mouse lung, Th1 immunity is the principal cause for changes in the Mycobacterium tuberculosis growth from exponential to non-replicating persistence during infection. The shift in bacterial growth in response to Th1 immunity is accompanied by changes in the transcription pattern of immunodominant bacterial proteins. These data imply that some similarities may exist between antigenic profiles expressed by M. tuberculosis in human and mouse infections. We propose that T cell responses elicited against alanine dehydrogenase and glutamine synthetase are protective. Additionally, vaccination against these bacterial proteins expressed during chronic infection in mouse lung may be more effective than vaccination against other targets expressed predominantly at initial phase of infection. This hypothesis will be tested in a low-dose aerosol infection model employing mice transgenic for human HLA-A2 allele. The timing of expression of these bacterial proteins relative to the onset of Th1 immunity, and the kinetics of expression of antigen-specific T cell responses will be characterized during infection with M. tuberculosis. The protective potential of T cell-mediated immune responses against these proteins will be determined in DNA vaccinated and challenged mice. Finally, the molecular targets of polyclonal cytotoxic T lymphocyte responses elicited by DNA vaccines against the whole protein will be identified in challenged mice. This knowledge is expected to open a new approach in designs of vaccines against M. tuberculosis.

描述（由申请方提供）：我们已获得证据表明，在人类中，与活动性疾病相关的抗原特异性免疫应答特征与潜伏性感染观察到的特征不同。HLA-A2限制性，Th 1型细胞毒性T淋巴细胞对分枝杆菌丙氨酸脱氢酶和谷氨酰胺合成酶的反应只能在未接种疫苗，结核菌素皮试阳性的无症状个体中检测到，但在活动性结核病患者中检测不到。在小鼠肺中，Th 1免疫是结核分枝杆菌在感染期间从指数生长到非复制持续生长的主要原因。响应于Th 1免疫的细菌生长的转变伴随着免疫显性细菌蛋白的转录模式的变化。这些数据表明，由M.人类和小鼠感染结核病。我们建议，T细胞反应引起的丙氨酸脱氢酶和谷氨酰胺合成酶是保护性的。此外，针对这些在小鼠肺部慢性感染期间表达的细菌蛋白的疫苗接种可能比针对主要在感染初始阶段表达的其他靶标的疫苗接种更有效。将在采用人HLA-A2等位基因转基因小鼠的低剂量气溶胶感染模型中检验这一假设。这些细菌蛋白表达的时间相对于Th 1免疫的开始，以及抗原特异性T细胞应答的表达动力学将在感染M.结核T细胞介导的针对这些蛋白质的免疫应答的保护潜力将在DNA接种和攻击的小鼠中确定。最后，针对全蛋白的DNA疫苗引起的多克隆细胞毒性T淋巴细胞应答的分子靶标将在攻击小鼠中被鉴定。这一发现有望为抗M.结核