This proposal is for the continuation of the collaborative investigation, of the effects of aging on immune responsiveness, of the laboratories of three senior investigators. The research accomplished by these laboratories has already contributed significantly to our understanding of changes in both T and B cell responsiveness associated with aging. This research has led to insights concerning the effects of increased anti-idiotypic reactivity on both B and T cell responsiveness, the consequences of relatively low levels of interleukin production by T cells of aged mice, changes in the repertoire of B cell variable regions per se that are associated with aging, and the consequences of the increase in auto-reactivity associated with aging with respect to both model auto-immune conditions such as experimentally induced thyroiditis and encephalomyelitis, as well as the potential effects of these changes in the etiology of degenerative coronary artery disease and myocardial infarction. The common interest of these three laboratories in the basis for the age associated increase in auto-immune recognition will continue as a major theme of all three proposals. The Weigle laboratory proposes to capitalize on their finding that T and B cells of aged mice which would not normally be responsive, can be made responsive with the addition of various interleukines. This should enable the examination of changes in responsiveness and autoimmune reactivity in populations of cells of aged animals heretofore unavailable for investigation. The Klinman laboratory will extend its investigation of repertoire expression and responsiveness to self antigens in aged animals to include two newly defined B cell subpopulations, secondary and Ly-1 B cells. The Dixon laboratory has identified individuals among auto-immune strains which display unexpected longevity. In one such strain, this trait breeds true. This finding provides an unique opportunity to identify both genetic and environmental factors which may contribute to longevity. The proposals of both the Dixon and Klinman laboratories are heavily oriented towards molecular biological analyses. In the Dixon Laboratory this approach will be used to identify changes in the genes potentially responsible for the longevity of autoimmune mice, and, in the Klinman Laboratory, molecular approaches will be used to identify the basis for novel repertoire expression in aged mice.
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