Mechanisms of reduced T cell imunity in older adults

老年人 T 细胞免疫力降低的机制

• 批准号: BB/H020519/1
• 负责人: Arne Akbar
• 金额: $ 67.48万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH020519%2F1
• 关键词: Mechanisms; reduced; cell; imunity; older

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.

老龄化伴随着对传染病的明显易感性，这些传染病给迅速老龄化的社会造成了生产力损失、医疗费用增加和生命损失等严重损失。随着年龄的增长，免疫系统的逐渐衰退-免疫衰老-是这种易感性与年龄相关的增加的主要潜在原因。尽管进行了数十年的研究，但在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方面仍然存在重大差距。一些关键的知识差距是由于研究免疫衰老的现有模型的整合不足，以及所获得的数据与人类衰老相关性的验证不完整。具体而言，两个最流行和最相关的模型-（免疫）遗传通用和易于操作的小鼠模型;以及伦理上更复杂和实验上有限，但生理上最相关的人类模型，迄今为止提供的数据彼此不兼容。该提案旨在通过利用共同申请人之一新开发的人类模型来研究健康年轻和老年供体皮肤中的记忆T细胞反应来缩小这一差距。我们最近的人体研究已经确定了老年人在皮肤中建立有效免疫反应的能力方面的一个重大缺陷。然而，这不是一个全球性的检测，因为来自同一个体血液的白色细胞可以对注射到皮肤中的相同微生物产品做出反应。然而，由于道德约束，对皮肤中有缺陷的细胞的实际操作不能在人类中进行。此外，不可能测试我们是否可以通过直接靶向体内称为巨噬细胞的缺陷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开发这种模型，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博士密切合作进行。因此，我们将在小鼠中开发相同的皮肤攻击实验系统，我们可以操纵该系统以尝试提高老年动物皮肤中的免疫力。在准备该提案期间，Akbar博士于2008年11月下旬访问了图森，Nikolich博士于2009年2月前往伦敦组织该申请的目标和策略。通过激烈的讨论和共同努力，我们开发了一种协同实验策略，将人类的尖端研究与小鼠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衰老过程中出现的皮肤免疫缺陷。

项目成果

Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis

• DOI: 10.3389/fimmu.2018.03001
• 发表时间: 2019-01-04
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Covre, Luciana P.;Martins, Regia F.;Gomes, Daniel C. O.
• 通讯作者: Gomes, Daniel C. O.

Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation.

通过阻断p38促丝分裂原激活蛋白（MAP）激酶诱导的炎症，增强皮肤免疫力。

• DOI: 10.1016/j.jaci.2017.10.032
• 发表时间: 2018-09
• 期刊: The Journal of allergy and clinical immunology
• 作者: Vukmanovic-Stejic M;Chambers ES;Suárez-Fariñas M;Sandhu D;Fuentes-Duculan J;Patel N;Agius E;Lacy KE;Turner CT;Larbi A;Birault V;Noursadeghi M;Mabbott NA;Rustin MHA;Krueger JG;Akbar AN
• 通讯作者: Akbar AN

Derivation of marker gene signatures from human skin and their use in the interpretation of the transcriptional changes associated with dermatological disorders.

• DOI: 10.1002/path.4864
• 发表时间: 2017-04
• 期刊: The Journal of pathology
• 作者: Shih BB;Nirmal AJ;Headon DJ;Akbar AN;Mabbott NA;Freeman TC
• 通讯作者: Freeman TC

Convergence of Innate and Adaptive Immunity during Human Aging.

• DOI: 10.3389/fimmu.2016.00445
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Pereira BI;Akbar AN
• 通讯作者: Akbar AN

CMV and Immunosenescence: from basics to clinics.

• DOI: 10.1186/1742-4933-9-23
• 发表时间: 2012-10-31
• 期刊: Immunity & ageing : I & A
• 作者: Solana R;Tarazona R;Aiello AE;Akbar AN;Appay V;Beswick M;Bosch JA;Campos C;Cantisán S;Cicin-Sain L;Derhovanessian E;Ferrando-Martínez S;Frasca D;Fulöp T;Govind S;Grubeck-Loebenstein B;Hill A;Hurme M;Kern F;Larbi A;López-Botet M;Maier AB;McElhaney JE;Moss P;Naumova E;Nikolich-Zugich J;Pera A;Rector JL;Riddell N;Sanchez-Correa B;Sansoni P;Sauce D;van Lier R;Wang GC;Wills MR;Zieliński M;Pawelec G
• 通讯作者: Pawelec G