Mechanisms of reduced T cell imunity in older adults

Lead Research Organisation: University College London
Department Name: Immunology and Molecular Pathology

Abstract

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.

Technical Summary

There are considerable gaps in understanding the behavior of both regulatory and effector cells during immune responses in vivo and crucial questions, especially in humans, remain unanswered. We previously developed a model to study a memory T cells response to antigen-injection in the skin of normal human volunteers (recall response); in this model we can perform histological investigations of infiltrating leucocytes at different times after antigen challenge, or study their function after isolation from suction blisters induced at the site of injection. This allows us to follow the course of a response from initiation to resolution and gives us access to the human tissues where immune response is taking place. In this study we want to investigate the kinetics with which different functional leucocyte populations accumulate and disappear in the skin during a cutaneous immune response during ageing. This grant is part of a BBSRC/NIH partnership into the study of ageing and Dr. Janko Nikoloch-Zugich is the parther in the USA who works on a complementaty skin immune response in ageing mice. Both humans and mice exhibit defective responses to cutaneous challenge with recall antigen during ageing. The experiments are designed to integrate the information gained when studying the mechanisms of immune ageing in different species. In particular as the use of the mouse model will inform on whether or not it is possible to reverse the defects in cells that lead to decreased responses to cutaneous immune challenge in old humans. Specifically this project will extensive use of flow cytometry, histological analysis of leucocytes in skin, in vitro assays of lymphocyte function ain humans. The project partner in the USA will perform extensive ananlysis of skin immunity of ageing mice in vivo.

Planned Impact

The proposed studies involve using a unique experimental system, developed largely through previous BBSRC funding, that enables the study of human immune responses in vivo. As these studies cannot be performed easily elsewhere, the data generated will be unique, important and relevant for all researchers who investigate human immunity, to indicate whether results that are normally assessed in blood leucocytes in vitro, also apply to immune responses in tissues. The fact that we have already published studies using this model in high impact journals (Reed et al J. Exp. Med. 2004, Vukmanovic-Stejic et al J. Clin. Inest 2008) supports this possibility. In addition, this proposal involves a partnership between the Akbar group that will use this human model to study immune ageing in the skin in vivo and the Nikolich-Zugich group that has an eminent track record in the study of ageing in mice. This will enable for the first time, the integration of information from 2 mammalian species, to allow the better understanding the similarities or differences in age-related immune responses in vivo. The impact of this that the information gained in the mouse will become more relevant for changes seen in the human. This will be of importance for researchers who work in either species in isolation, where the data will obtained will inform on the extent to which results obtained can be extrapolated. These studies of cross-relatedness of immunity between species will be important for Bio-Pharmaceutical industries especially for therapeutic drug development and will bridge the knowledge gap between responses in animals and those in humans. Furthermore with the demographic shift in populations worldwide to an older age, the integration of data from cross-informative studies will enable to determine in mice, the extent to which mechanisms of immune decline can be targeted to improve health in humans. Finally with the BBSRC priority to reduce animal experimentation, it would be important to maximize the impact of results on immunity in animals by showing that they are relevant to ageing in humans.

Publications

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Griffiths SJ (2013) Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA. in Journal of immunology (Baltimore, Md. : 1950)

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Pereira BI (2016) Convergence of Innate and Adaptive Immunity during Human Aging. in Frontiers in immunology

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Solana R (2012) CMV and Immunosenescence: from basics to clinics. in Immunity & ageing : I & A

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Vukmanovic-Stejic M (2013) Varicella zoster-specific CD4+Foxp3+ T cells accumulate after cutaneous antigen challenge in humans. in Journal of immunology (Baltimore, Md. : 1950)

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Vukmanovic-Stejic M (2015) The Characterization of Varicella Zoster Virus-Specific T Cells in Skin and Blood during Aging. in The Journal of investigative dermatology

 
Title Akbar Film 
Description Video of Research Activities in The Akbar Group 
Type Of Art Film/Video/Animation 
Year Produced 2015 
Impact The film is used by the Akbar laboratory and its members when advertising our research and its impact. It has been shown at public engagement events and used when advertising new opportunities to join the group. 
URL https://youtu.be/l_426Pamxcc
 
Description The key aim of the grant was to determine whether there were any similarities between current models of mouse and human antigen-specific cutaneous responses. Our studies show current mouse models that have been used do not reflect the human DTH model. Nevertheless we found prelimiary data that suggests that other murine models may be more representative of human immunity.



1.In humans, we have found that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. This is not due to a change in T cells in terms of their capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject which prevents memory T cell entry into the skin after antigen challenge. This is due to the lack of inflammatory mediators (such as TNF-alpha) in the old skin.

2. Once isolated cutaneous macrophages can be induced to secrete TNF-alpha after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro; This indicates that the defect in their ability to activate the endothelium is reversible.Therefore the lack of macrophage activation is not characteristic of macrophages themselves but is possibly a consequence of the changes in the skin milieu in old individuals and/ or lack of early activating signals which come from another cell types and then fail to become amplified.

3. There is no difference in the number or positioning of CD4 cells and macrophages or DCs in the old skin. The only difference observed is the increased proportion of CD4 cells expresisng Foxp3 which have regulatory function. The capacity of skin resident T cells from the old skin to respond to mitogens appears to be uneffected. We are currenlty examining their capacity to respond to recall antigens.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Microarray data generation 
Organisation Rockefeller University
Country United States 
Sector Academic/University 
PI Contribution Collaboration with a group at the Rockefeller University, to generate and analyse microarray data of normal and antigen challenged human skin from young and old individuals to investigate the mechanisms for age related changes in cutaneous immunity.
Start Year 2008
 
Description Sanofi-Pasteur Collaboration 
Organisation Sanofi Pasteur MSD
Country United Kingdom 
Sector Private 
PI Contribution Sanofi-Pasteur have provided £15000 for the study of effects of Zostavax vaccine on the skin and blood responses to Varicella Zoster Virus in old individuals
Start Year 2013