Mechanisms of reduced T cell imunity in older adults

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.

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.

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.