Novel targets for vaccines against tuberculosis

描述(由申请人提供)：我们已经获得证据表明，在人类中，与活动性疾病相关的抗原特异性免疫反应的特征与观察到的与潜伏感染相关的不同。针对分枝杆菌丙氨酸脱氢酶和谷氨酰胺合成酶的HL-A2限制性Th1型细胞毒性T淋巴细胞反应只能在未接种疫苗、结核菌素皮肤试验阳性的无症状患者中检测到，而在活动性结核病患者中检测不到。在小鼠肺中，Th1免疫是结核分枝杆菌在感染期间从指数增长转变为非复制持续生长的主要原因。细菌生长对Th1免疫反应的转变伴随着免疫优势细菌蛋白转录模式的变化。这些数据表明，结核分枝杆菌在人类和小鼠感染中表达的抗原谱之间可能存在一些相似之处。我们认为，针对丙氨酸脱氢酶和谷氨酰胺合成酶的T细胞反应是保护性的。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可能比针对主要在感染初期表达的其他靶点的疫苗更有效。这一假设将在低剂量气雾剂感染模型中得到验证，该模型使用的是转人类HLA-A2等位基因的小鼠。这些细菌蛋白的表达时间与Th1免疫的开始相关，以及抗原特异性T细胞反应的表达动力学将在感染结核分枝杆菌期间进行表征。T细胞介导的免疫反应对这些蛋白的保护潜力将在DNA疫苗和挑战小鼠中确定。最后，针对整个蛋白的DNA疫苗将在受攻击的小鼠中识别多克隆细胞毒性T淋巴细胞反应的分子靶点。这一知识有望为结核分枝杆菌疫苗的设计开辟一条新途径。

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.