IMMUNOLOGICAL TOLERANCE AND AGING

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Aging is accompanied by an altered immunoregulatory state characterized by reduced responsiveness to neoantigens and increased formation of autoantibodies due to the breakdown of self tolerance. Studies from this laboratory have shown that acquired immunological tolerance is readily aborted in the presence of gram negative bacterial endotoxin in aged mice. Modulation of the immune system by endotoxin is orchestrated by interleukin-1 (IL-1). IL-1 is a small protein produced by mononuclear phagocytes in response to a variety of stimuli including endotoxin. This is the purpose of the present studies to explore the thesis that aged mice are hyperreactive to IL-1. The effects of IL-1 on the development and maintenance of acquired immunological tolerance to a heterologous serum protein will be studied in young adult (2 months), middle aged (12 months) and old (24 months) mice. An acute exposure at the time of tolerance induction and chronic exposure afforded by implanted constant release capsules will be investigated. In addition, an in vitro model of tolerance induction will be studied in the presence and absence of added IL-1. Aged mice have been shown to be more sensitive to the pyrogenic effects of both endotoxin and IL-1. The role of hypo- and hyperthermia on the induction of tolerance and of antibody formation in splenocytes from mice of different ages will be investigated using in vitro systems. IL-1 also orchestrates the acute phase response which is characterized by altered serum concentration of divalent cations and proteins and increased numbers of circulating neutrophils. Very little is known about the acute phase response in aging and how its various components might affect the immune system. In the present studies, the induction of serum amyloid A protein synthesis, reduction of serum levels of iron and levels of circulating neutrophils will be studied in mice of different ages given acute or chronic exposure to IL-1. Further experiments are designed to investigate the nature of the fundamental change which accounts for the age-related increased responsiveness to IL-1. Two possible mechanisms will be explored.