ALTERNATIVE APPROACH TO DEVELOPMENT OF A TB VACCINE

产品说明： 必须研制出能普遍预防 分枝杆菌病 这项任务似乎是可以实现的，因为目标 细胞免疫反应的分枝杆菌最近已被定义。 Hsp 65编码的表位代表了主要的抗原位点。 自从CTL 特异于肌细菌HSP呈现两种有益的活性模式， 即它们消除了感染病灶，降低了 释放的细菌，建议开发一种确定的亚单位疫苗 其将I类MHC限制性CTL提高至hsp肽。 然而，天然存在的hsp-反应性CTL显示交叉反应性， 在应激细胞中内源产生的宿主蛋白质。 因此， 用分枝杆菌hsp-65作为免疫原可诱导自身反应性CTL 有可能引发自身免疫性疾病 这个问题可以 如果一个人可以获得一种成分疫苗， 诱导对细菌hsp特有的表位具有特异性的CTL， 而不是细菌和真核HSP。 自从I类的研究 MHC分子表明，与MHC分子结合的非相关肽 MHC分子可能呈现足够接近的结构，以被 同样的TCR，我们建议开发一种针对细菌热休克蛋白的疫苗， 一个不相关的，即，非热休克蛋白抗原。 这一战略被用来 避免与自身蛋白质的交叉反应。 在其他情况下，同样 这种策略可能会提高对不能使用的抗原的反应， 由于它们的生物活性，例如毒性， 我们已经确定了一种候选疫苗能够提高I类MHC- 对细菌HSP 65的选择性限制反应。在小鼠中， 无关抗原，鸡卵清蛋白，一致性激发CTL特异性 对于分枝杆菌hsp 65-肽， 鼠同源物。 这些CTL有效地裂解细菌感染的细胞。 由于卵清蛋白的非感染性制剂和特异性 卵清蛋白肽是这些I类MHC的有效免疫原， 限制性反应，我们将检查是否注射这种抗原 可以保护动物免受两种模式病原体的感染， 单核细胞增多症和牛分枝杆菌（BCG），已被用作模型 用于分枝杆菌疾病。

DESCRIPTION: Vaccines have to be developed that provide universal protection against mycobacterial diseases. This task seems to be approachable since targets of the cellular immune response to mycobacteria have recently be defined. Hsp 65-encoded epitopes represent the major antigenic sites. Since CTL specific for myobacterial hsp present two beneficial modes of activity, i.e. they eliminate the foci of infection and decrease the viability of released bacteria, it is proposed to develop a defined subunit vaccine that raises class I MHC restricted CTL to an hsp peptide. However, naturally occurring hsp-reactive CTL show cross-reactivity on host proteins endogenously produced in stressed cells. Thus, the direct use of mycobacterial hsp-65 as immunogen might elicit auto-reactive CTL potentially prone to initiate auto-immune diseases. This problem can be alleviated if one has access to a component vaccine that selectively induces CTL with specificities to epitopes unique to bacterial hsp, rather than bacterial and eukaryotic hsp. Since studies of the class I MHC molecules have suggested that un-related peptides bound to the same MHC molecule might present structures close enough to be recognized by the same TCR, we propose to develop a vaccine against bacterial hsp using an un-related, i.e., non-hsp, antigen. This strategy is employed to avoid cross-reactivity to self-proteins. In other situations, the same strategy might allow to raise responses to antigens that cannot be used by themselves due to their biological activity, e.g, toxicity. We have identified a candidate vaccine that is able to raise class I MHC- restricted responses selectively to bacterial hsp 65. In mice, this unrelated antigen, chicken ovalbumin, consistently elicits CTL specific for an mycobacterial hsp 65-peptide with no cross-reactivity to the murine homologue. These CTL effectively lyse bacterially infected cells. Since non-infectious preparations of ovalbumin and the specific ovalbumin-peptide are efficient immunogens for these class I MHC- restricted responses, we will examine whether injection of this antigen can protect animals against infection with two model pathogens, listeria monocytogenes and mycobacteria bovis (BCG), that have been used as models for mycobacterial diseases.