HORMONAL RESTORATION OF A FUNCTIONAL THYMUS DURING AGING

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DESCRIPTION: (Adapted from applicant's abstract): Macrophages from aged rats are unable to respond to the classic T cell-derived cytokine, interferon-gamma (IFN-gamma), in vitro, as assessed by their failure to secrete superoxide anion and tumor necrosis factor-alpha (TNF-alpha). More importantly, syngeneic pituitary grafts, which secrete growth hormone, can reverse these defective responses of macrophages from aged rats to IFN-gamma. Since the synthesis of growth hormone, as well as its growth-promoting peptide, insulin-like growth factor-I (IGF-I), decline dramatically in aged animals and humans, these new results suggest that classical pituitary hormones from the neuroendocrine system play an important role in the aberrant immune responses of aged subjects. In young animals, growth hormone has recently been discovered to augment a number of immune responses, including macrophage and neutrophil activation. Unfortunately, a detailed analysis of macrophage activation in aged subjects has not been investigated. Dr. Kelley and coworkers now propose to systematically evaluate the activation of phagocytic cells by recombinant IFN-gamma in both aged rats and humans and to explore the role of both growth hormone and IGF-I in this process. The ability of recombinant IFN-gamma, growth hormone and IGF-I to activate macrophages of aged rats will be assessed in vitro by secretion of superoxide anion, TNF-alpha, antigen presentation to cloned T lymphocytes, expression of class II genes of the MHC, synthesis of IL-1 and IL-6 and bacterial and tumor killing. Similar studies will then be conducted by injecting recombinant growth hormone into aged rats. These findings will be extended to aged humans by determining whether polymorphonuclear cells from these subjects can be primed as well as those from young donors by IFN-gamma, growth hormone or IGF-I to produce superoxide anion and kill bacteria and tumor cells. To investigate the cellular mechanisms by which growth hormone and IGF-I are able to prime phagocytic cells, genetically-engineered variants of growth hormone will be used to elucidate the domain that is critical for binding to its receptor on human neutrophils, and whether expression of this receptor declines in aged subjects. The possibility that growth hormone and IGF-I act to reverse defective responses of macrophages from aged rats by increasing the number of IFN-gamma receptors on macrophages will be determined. Solution hybridization ribonuclease protection and nuclear run-on assays will be used to learn whether the reduction in TNF-alpha by IFN-gamma primed macrophages from aged rats is associated with a reduction in rate of transcription of this gene. Similar experiments will be conducted for the heavy chain of cytochrome b 558 and the Aalpha chain of class II MHC molecules. Finally, the investigators will use reverse polymerase chain technology to determine if activated macrophages actually synthesize IGF-I and if expression of macrophage-derived IGF-I declines during aging. These experiments will be the first to investigate the role of both a recombinant pituitary hormone and IFN-gamma on activation of phagocytic cells from aged animals, and thereby provide important, new information about functional activities of macrophages and neutrophils during aging.