Modulation of antigen processing and cross presentation by endogenous and exogenous heat shock proteins for stimulation of CTL-mediated immunity.

免疫系统的功能是识别和消除引起疾病的传染因子。在利用疫苗保护人类和动物免受传染病侵害方面取得了相当大的成功。然而，需要新的疫苗接种方法和对增强免疫反应强度的方法有更深入的了解，以预防新疾病和消除免疫系统无法很好地识别的感染。新的疫苗配方和刺激免疫反应的改进方法也有可能预防甚至消除某些癌症。强效免疫是由“杀手”T细胞介导的，它可以直接破坏被病毒或细菌感染的靶细胞，或者被认为是异常的靶细胞，如肿瘤细胞。被免疫系统识别的感染因子或异常细胞的成分是在细胞内产生的，必须在细胞外进行处理和展示，才能被T细胞识别。我们目前认为，被称为树突状细胞的免疫细胞也必须获得被感染细胞的成分，可能是通过“吃掉”类似被感染细胞的碎片，并利用这些外来碎片教会一些T细胞成为杀伤T细胞。已经发现感染细胞和肿瘤细胞中的一些热诱导蛋白会增加对杀伤T细胞的刺激。该研究项目将研究靶细胞和树突状细胞产生热诱导蛋白的影响，以诱导对靶细胞中表达的病毒成分产生强烈的杀伤T细胞反应。靶细胞或“吃掉”靶细胞的树突状细胞将被用作疫苗，以测试是否产生对“感染”细胞的免疫力。此外，树突状细胞的变化，诱导强烈的杀伤T细胞反应，对修饰的靶细胞，将被充分分析。这些实验将揭示增强对细胞内成分免疫的机制，并将确定改进下一代保护性疫苗设计的方法。

The immune system functions to recognize and eliminate infectious agents that cause disease. Considerable success has been achieved in protecting humans and animals against infectious diseases with the use of vaccines. However, new methods of vaccination and greater understanding of ways to boost the strength of immune responses are needed to protect against new diseases and to eliminate infections that are not well seen by the immune system. New vaccine formulations and improved methods to stimulate immune responses also have the potential to protect against, and even eliminate, some cancers. Potent immunity is mediated by 'killer' T cells, which can directly destroy target cells that are infected by virus or bacteria, or that are otherwise recognized as abnormal, such as tumour cells. The components of the infectious agent or abnormal cell that are recognized by the immune system are made inside the cell, and have to be processed and displayed outside the cell to be recognized by T cells. We currently believe that immune cells called dendritic cells must also acquire the components of the infected cells, probably by 'eating' fragments of similarly infected cells, and use these foreign fragments to teach some of the T cells to become killer T cells. Some heat-induced proteins in infected cells and tumour cells, have been found to increase the stimulation of killer T cells. This research project will examine the effects of production of heat-induced proteins by target cells and dendritic cells, on inducing a strong killer T cell responses against a component of a virus which is expressed in the target cells. The target cells, or dendritic cells which have 'eaten' the target cells, will be used as a vaccine to test whether immunity against the 'infected' cells is generated. Also, the changes in the dendritic cells that induce strong killer T cell responses against the modified target cells, will be fully analysed. These experiments will reveal mechanisms that enhance immunity to intracellular components and will identify ways to improve the design of the next generation of protective vaccines.