Mechanisms of reduced T cell imunity in older adults

老龄化伴随着对传染病的明显易感性，这些疾病在生产力丧失、保健费用增加和生命丧失方面给迅速老龄化的社会造成了沉重的代价。随着年龄的增长，免疫系统的逐渐衰退——免疫衰老——是这种易感性随年龄增长而增加的主要潜在原因。尽管进行了数十年的研究，但我们对这一过程的基本性质的理解以及我们保护老年人免受传染病侵害的实际能力仍然存在重大差距。一些关键的知识缺口是由于研究免疫衰老的现有模型整合不足，以及所获得的数据与人类衰老的相关性验证不完整。具体来说，两种最流行和最相关的模型-（免疫）基因通用和易于操作的小鼠模型；伦理上更复杂，实验上更有限，但生理学上极其相关的人类模型，迄今为止提供的数据彼此之间还不够兼容。该提案旨在通过利用共同申请者之一新开发的人体模型来缩小这一差距，以研究健康的年轻和老年供者皮肤中的记忆T细胞反应。我们最近的人体研究发现，老年受试者在皮肤上产生有效免疫反应的能力存在显著缺陷。然而，这并不是一个全球性的发现，因为来自同一个人血液中的白细胞可以对注射到皮肤中的同一种微生物产物产生反应。然而，由于伦理限制，对皮肤中有缺陷的细胞的实际操作不能在人类身上进行。此外，在体内，我们无法测试是否可以通过直接靶向缺陷细胞巨噬细胞上的细胞表面活化受体（Toll受体）来增强这些细胞的反应。我们建议在人类中进一步深入发展这一模型，并扩大、增强和补充在老年小鼠皮肤免疫模型中平行使用的机制研究所产生的数据，这些研究将与亚利桑那大学的Janko Nikolich-Zugich博士密切合作。因此，我们将在老鼠身上开发同样的皮肤挑战实验系统，我们可以操纵它来尝试提高老年动物皮肤的免疫力。在准备这项提案的过程中，阿克巴博士于2008年11月下旬访问了图森，而尼克里奇博士则于2009年2月前往伦敦，为这项申请组织目标和策略。通过激烈的讨论和共同努力，我们已经制定了一项协同实验策略，将在人类身上进行的尖端研究与在小鼠身上进行的平行研究联系起来，从而能够在体内操纵衰老的免疫系统，以确定我们是否可以逆转在衰老过程中产生的皮肤免疫缺陷。

Aging is accompanied by a marked susceptibility to infectious diseases, which inflict heavy toll upon the rapidly aging society with regard to lost productivity, mounting health costs and loss of life. The progressive decline with age of the immune system - immunosenescence - is the primary underlying cause of the age-related increase in this susceptibility. Despite decades of research, important gaps remain in our understanding of the fundamental nature of the process, as well as in our practical ability to protect older adults against infectious diseases. Some of the key gaps in knowledge result from the insufficient integration of the available models in which to research immunosenescence, and incomplete validation of the relevance of obtained data to the human aging. Specifically, the two most popular and most relevant models - the (immuno)genetically versatile and easily manipulated mouse model; and the ethically much more complex and experimentally limited, but physiologically supremely relevant human model, have provided data that is insufficiently compatible with one another thus far. This proposal seeks to reduce this gap by taking advantage of the newly developed human model by one of the co-applicants, to study memory T cell response in the skin of healthy young and old donors. Our recent human studies had identified a significant defect in the ability of old subjects to mount an eficient immune response in the skin. However this is not a global deect as the white cells from the blood of the same individuals can respond to the same microbial product that was injected in the skin. However the actual manipulation of the cells that are defective in the skin cannot be performed in humans due to ethical constraints. Furthermore, it is not possible to test whether we can enhance the responses of these cells by directly targeting cell surface activatory receptors (Toll receptors) on the cell that is defective called macrophagethe in vivo. We propose to further develop in depth this model in humans and to broaden, enhance and complement the data generated by the parallel use of mechanistic studies in the aged mouse model of skin immunity that will be performed in close partnership with Dr. Janko Nikolich-Zugich at the University of Arizona. Thus we will develop he same skin challenge experimental system in the mouse that we can manipulate to attempt to boost immunity in he skin in old animals. During the preparation of this proposal, Dr Akbar had visited Tucson in late November, 2008, and Dr. Nikolich travelled to London in February 2009 to organize the aims and strategy for this application. From the intense discussions and joint efforts, we have developed a synergistic experimental strategy, whereby incisive, cutting-edge studies in humans will be linked to parallel investigations in mice to enable the manipulation of the ageing immune system in vivo to determine if we can reverse the cutaneous defect in cutaqneous immunity that develops during ageing.