The objective of the present proposal is to establish the effects of aging on the cellular and subcellular events that are associated with self-nonself recognition and autoimmunity. These objectives will be approached by investigating the effects of aging in mice on the induction and stability of immunological tolerance. The ease with which tolerance is induced in young adult and aged mice will be established in the T helper (Th) and B cells which are more drastically affected by the aging process rather than those which escape it. Thus, conditions required for tolerance induction in aged mice will be established in both T helper (Th) cells and in B cells, using probes which allow the expression of otherwise immune-compromised aged cells. The studies on the induction of tolerance will be facilitated by the establishment of Th cell clones from aged mice. Clones will be generated from both cells that are affected by the aging process and those which escape aging. In the former case, clones will be generated from T cells which are not normally expanded following antigen activation in vivo, but can be expanded in vitro by the addition of IL-2. In addition, two experimental models of autoimmunity, i.e., experimental autoimmune thyroiditis (EAT) and experimental allergic encephalomyelitis (EAE) will be studied to determine the effect that aging has on both the initiation of autoimmunity and the secondary events that lead to tissue damage. The effect of aging will be determined for both the initiation of immune responses by autoantigen-specific L3T4+ cells and the ability of cloned T cells generated from both the aged and young adult mice to act as effector cells causing tissue damage. The effect of aging on the generation of T suppressor (Ts) activity will also be assessed as well as the effect of such T cells on generation of autoimmunity and its expression in the form of tissue damage. It will also be determined whether lymphoid tissue draining the thyroid is spared by the aging process and thus responsible for the development of thyroid lesions in otherwise immune compromised aged mice.
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