Immunorejuvenation in the elderly





Graham Pawelec [1], Sven Koch [1], Cécile Gouttefangeas [2] and Anders Wikby [3]

[1] Zentrum für Medizinische Forschung, ZMF, University of Tübingen, Waldhörnlestr 22, D-72072 Tübingen, Germany [2] Department of Immunology, University of Tübingen, Tübingen, Germany [3] Department of Natural Science and Biomedicine, University College of Health Sciences, Jönköping, Sweden



Dysregulated T cell-mediated immunity contributes materially to the increased susceptibility to infectious disease, and possibly cancer, in the elderly. One hallmark of this state of "immunosenescence" is the predominance of large clones of peripheral T cells with limited antigen receptor heterogeneity and a corresponding contraction of diversity in the T cell antigen recognition repertoire. Consensus is now developing that a major driving force for these clonal expansions in humans is a limited number of viral antigens, commonly derived from persistent Herpes viruses, especially Cytomegalovirus (CMV). This was completely unexpected, because CMV is a widespread virus generally considered non-pathogenic except in immunosuppressed individuals. However, there is little evidence that the elderly are overtly immunosuppressed, and they do not suffer CMV exacerbations any more frequently than the young. We have shown that the elderly actually maintain larger numbers of functional CMV-specific T cells than the young, reflecting the vital importance of constant immunosurveillance against this virus. The human immune system is thus subjected to chronic antigenic stress caused by persistent activating virus, which can never be fully eliminated. This constant stimulation results in clonal exhaustion of the CMV-specific cells, a state of anergy which is similar in many respects, and, we believe for similar reasons, to that commonly seen in the tumour-specific T cells of cancer patients. The problem which we have identified in a subset of the elderly (those falling into what we have designated the "Immune Risk Profile", or IRP, category) is not a lack of functional CMV-specific cells, but an enormous excess of persisting dysfunctional CMV-specific cells. That is, these cells are apoptosis-resistant, anergic, and are passively suppressive by filling the "immunological space", as well as potentially actively suppressive via cytokine secretion. The accumulation of these dysfunctional cells is, we believe, one of the major problems in the elderly immune system. Moreover, because these cells by persisting maintain overall T cell numbers in the periphery, T cell homeostasis mechanisms feed back to the thymus to prevent the production of naive functional T cells specific for other antigens. This, coupled with the age-associated process of thymic involution, results in shrinkage of the T cell antigen repertoire in the elderly, and contributes to increased susceptibility to infections, especially to newly-arising infectious agents not experienced by that individuals "young" immune system in the past.

What can be done to improve this state of affairs? The most obvious approach would be to employ anti-CMV vaccinations on a broad scale, and other anti-viral therapies. For those already at a more advanced age (and such CMV-driven clonal expansions are already becoming detectable in many middle-aged people), treatment targeting the dysregulated apoptosis-resistant CMV-specific cells would be an option. This would require distinguishing the functional CMV-specific cells (which are essential to maintain immunosurveillance) from the dysfunctional ones. We have discovered certain surface molecules on dysfunctional cells which may enable us to achieve this aim. Capitalising on technology now essentially routinely applied in hematopietic stem cell transplantation, functional anti-CMV effector cells could be first isolated and expanded in vitro, prior to re-infusion into the depleted individual, as a safety measure to ensure and enhance CMV immunosurveillance during and after specific depletion. These approaches, coupled with the application of methods being investigated by others, directed at reinvigorating the thymus (eg. use of interleukin 7), might result in a degree of "immunorejuvenation" sufficient to take elderly individuals out of the IRP category (which otherwise, once entered, is in our experience never left again and predicts incipient mortality) and thereby extend healthy longevity.




Key words: immunosenescence; immune risk profile; clonal exhaustion; T cells; Cytomegalovirus







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