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Reconstitution of normal immune function in old age is generally based on boosting the response against foreign antigens, e.g. infectious microorganisms. Our focus, however, will be to normalise immune reactivity by correcting the immune dysregulation which starts early, but is known to increase with age and form the basis of important age related diseases with high costs to European societies in terms of morbidity and mortality. Paradigmatic age related diseases that form the focus of this proposal are atherosclerosis (AT) and rheumatoid arthritis (RA).

The project is to look at novel approaches to normalise immune function at old age on three complementary levels.
1) The first of these is to look into the basic mechanisms of age-related changes in immune function, concentrating on thymic self-antigen display, T cell selection of autoreactive T cells, effects of aging on regulatory T cells (Treg), hormonal influences (particularly glucocorticoids - GC), and the action of cytokines in aging organisms.
2) The second part of the project will focus on two paradigmatic age related diseases, AT and RA, investigating in detail the effect of aging on the autoimmune reaction to heat shock protein 60 (HSP60), which has been shown to be an important autoantigen in both AT and RA. In particular, attempts will be made to jointly apply knowledge from research groups engaged in the first part by inducing tolerance to HSP60 in mouse models of both AT and RA at various ages and disease stages. The knowledge gained of how the immune system ‘ages’ will then be used to focus and fine tune efforts inducing tolerance towards HSP60.
3) The third element, the identification of the mechanisms responsible for a normalisation of the immune response after appropriate intervention (e.g. nasal/oral tolerance) on the cellular level, is an important practical component of the project. Investigations elaborating the mechanisms responsible for tolerance are to address the role of central and peripheral deletion of T cells, the action of Treg cells, the balance of immune regulatory cytokines, and hormonal (GC) influences during the aging process.