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显着易感性，这给迅速老龄化的社会造成了严重的损失，包括生产力下降、医疗费用增加和生命损失。免疫系统随着年龄的增长而逐渐衰退——免疫衰老——是这种易感性随年龄增长而增加的主要原因。尽管经过了数十年的研究，我们对该过程的基本性质的理解以及我们保护老年人免受传染病的实际能力仍然存在重大差距。知识方面的一些关键差距是由于研究免疫衰老的可用模型的整合不充分以及所获得的数据与人类衰老的相关性验证不完整造成的。具体来说，两种最流行和最相关的模型 - （免疫）遗传多功能且易于操作的小鼠模型；而伦理上更为复杂且实验有限但生理上极其相关的人类模型所提供的数据迄今为止彼此还不够兼容。该提案旨在通过利用共同申请人之一新开发的人体模型来研究健康年轻和年长捐赠者皮肤中的记忆 T 细胞反应，从而缩小这一差距。我们最近的人体研究发现，老年受试者在皮肤中产生有效免疫反应的能力存在重大缺陷。然而，这并不是一种全球性缺陷，因为来自同一个人血液的白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，由于伦理限制，无法在人类身上对皮肤有缺陷的细胞进行实际操作。此外，无法测试我们是否可以通过直接靶向体内有缺陷的巨噬细胞上的细胞表面激活受体（Toll 受体）来增强这些细胞的反应。我们建议进一步深入开发人类模型，并扩大、增强和补充通过并行使用老年小鼠皮肤免疫模型的机制研究所产生的数据，该模型将与 Janko Nikolich-Zugich 博士密切合作进行在亚利桑那大学。因此，我们将在小鼠中开发相同的皮肤挑战实验系统，我们可以操纵该系统来尝试增强老年动物皮肤的免疫力。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，组织了该应用的目标和策略。经过激烈的讨论和共同努力，我们制定了一种协同实验策略，将人类深入、前沿的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

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

• 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

Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA.

• DOI: 10.4049/jimmunol.1203267
• 发表时间: 2013-06-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Griffiths SJ;Riddell NE;Masters J;Libri V;Henson SM;Wertheimer A;Wallace D;Sims S;Rivino L;Larbi A;Kemeny DM;Nikolich-Zugich J;Kern F;Klenerman P;Emery VC;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