Immunoregulatory and Adjuvant effects of Hormones on the

Aging

Investigators

Linked publications & trials

Abstract

Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. A series of clinical studies have revealed that elderly subject, in contrast to their younger counterparts, exhibit poor cellular and humoral immune responses to vaccines even in the presence of standard adjuvants. Currently, many laboratories are focusing their research efforts into developing more effective adjuvants for use in elderly populations. We have also approached this problem by utilizing GM-CSF and various chemokines as vaccine adjuvants in aging rodent models resulting in increased vaccine-specific immune responses. Moreover, our laboratory in collaboration with various investigators at the National Cancer Institute has demonstrated that both prolactin and human growth hormone potentiate human and rodent lymphocyte activation and proliferation in response to various antigens and stimuli both in vitro and in vivo. These hormones have also been shown to modulate a variety of leukocyte functions including potentiating neutrophil killing of bacteria and yeast, lymphocyte activation to specific antigens and immune stimuli, modulating cytokine production, enhancing natural killer cell activity, thymic engraftment and regeneration, mast cell and granulocyte degranulation, and augmenting antibody production. Continuing efforts are underway to initiate hormone infusion studies in young and older subjects to examine their role as immunoadjuvants and effects on thymic regeneration. We have also initiated studies using young and aged mice to examine the effects of these pituitary hormones on thymic structure and regeneration. Given recent reports demonstrating a partial reversal of thymic involution and an increase in thymic cellularity in 12-16-month old mice post growth hormone treatment, we have focused our efforts on the effects of intrathymic and systemic growth hormone, prolactin and growth hormone secretagogues administration on thymic cellularity, structure, and activity within mice of varying ages. Such studies may lead to possible clinical strategies by which we can facilitate thymic regeneration and thus improve immune responses in the elderly. Recently, we have also initiated studies examining the function and antagonistic relationship between the orexigenic hormone, ghrelin and the anorexigenic hormone, leptin within the immune system. Grehlin, a recently described endogenous ligand for growth hormone secretagogue receptors (GHS-R), is produced from stomach serving as a potent circulating orexigen controlling energy expenditure, adiposity and GH secretion. The GHS-R are expressed in variety of tissues including lymphoid system; however, functional relevance of these receptors in immune system remains to be established. We have recently found that both GHS-R and ghrelin are expressed in human T cells, monocytes and PBMCs and specifically localize in GM1 rafts. Grehlin expression and production is increased by cellular activation. Moreover, ghrelin exerts specific potent inhibitory effects on inflammatory cytokines, IL-1 b, IL-6 and TNF-a but not TGF-b expression through functional GHS-R on human peripheral blood mononuclear cells and T lymphocytes. In contrast, leptin is known to inhibit feeding and appears to exert a proinflammatory effects in rodents. Given the believed mutually antagonistic effects of leptin and ghrelin, we next demonstrated that these hormones differentially regulate proinflammatory cytokine production. Ghrelin inhibits leptin-induced increments in these cytokines in a dose-dependent manner. Also, we have recently demonstrated that leptin directly modulates the expression of GHS-R expression on human T cells and PBMCs. Our results provide evidence for previously unknown immunoregulatory function of ghrelin and suggest that ghrelin might be a novel target for management of wasting associated with chronic inflammation, cancers and age.