ALTERNATIVE APPROACH TO DEVELOPMENT OF A TB VACCINE

说明： 必须开发出具有普遍保护作用的疫苗。 分枝杆菌病。这项任务似乎是可以接近的，因为目标 最近对分枝杆菌的细胞免疫反应进行了定义。 HSP65编码的表位是主要的抗原位点。自CTL以来 针对肌杆菌热休克蛋白呈现两种有益的活性模式， 也就是说，它们消除了感染的焦点，降低了 释放细菌，建议开发一种明确的亚单位疫苗 这将使I类MHC限制性CTL上升到HSP多肽。 然而，自然产生的热休克蛋白反应性CTL在 应激细胞内源性产生的宿主蛋白。因此，直接 分枝杆菌HSP-65作为免疫原可能诱发自身反应性CTL 有可能引发自身免疫性疾病。这个问题可能是 如果一个人能够获得一种成分疫苗，选择性地 诱导具有细菌HSP特有表位特异性的CTL， 而不是细菌和真核热休克蛋白。因为我班的学习 MHC分子已经表明，与MHC无关的多肽与 MHC分子可能呈现出足够近的结构，足以被 同样的TCR，我们建议开发一种针对细菌性HSP的疫苗，该疫苗使用 不相关的，即非热休克蛋白的抗原。这一策略被用于 避免与自身蛋白质发生交叉反应。在其他情况下，情况相同 策略可能允许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，它们本身也是如此。 我们已经确定了一种候选疫苗，能够提高I类MHC- 选择性地限制对细菌热休克蛋白65的反应。在老鼠身上，这是 无关抗原，鸡卵清蛋白，持续诱导CTL特异性 对于分枝杆菌热休克蛋白65-肽，与 小鼠的同源物。这些CTL有效地溶解细菌感染的细胞。 由于非感染性制剂的卵清蛋白和特异性 卵白蛋白多肽是这些I类MHC的有效免疫原。 限制反应，我们将检查是否注射这种抗原 可以保护动物免受李斯特菌这两种模型病原体的感染 单核细胞增多症和牛分枝杆菌(BCG)，已被用作模型 用于治疗分枝杆菌疾病。

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.