Growing evidence indicates a reciprocal relationship between the HPA axis and the immune system which may be relevant to disease expression. Since patients with AIDS exhibit abnormalities in the HPA axis, a thorough understanding of the basic physiology of neuroendocrine-immune interactions is an important prerequisite for determining the potential role of neuroendocrine function in the development of this disease. Nevertheless, adrenal steroid hormones, the final product of HPA axis activation, have complicated and inconsistent effects on in vivo immune function. Recent studies in our laboratories suggest that further understanding of these complex yet important immunologic effects of adrenal steroids will be greatly enhanced by focusing on adrenal steroid receptors in immune cells and tissues. Our results indicate that Type I and II adrenal steroid receptor binding is differentially expressed in various immune tissues and there is considerable heterogeneity between immune tissues in receptor subtype activation following in vivo hormone exposure. Moreover, we have found a highly significant relationship between adrenal steroid receptor activation in vivo and immune function. These findings in conjunction with the proposed studies will advance our knowledge of the mechanisms involved in the interaction between adrenal steroids and the immune response.
The specific aims of the proposed project are as follows: Except where indicated, all experiments will be conducted on Sprague Dawley rats.
For Specific Aim 1, the distribution of Type I and II receptor positive cell types in sections of spleen, thymus and mesenteric lymph nodes will be antibodies. In addition, these antibodies will be used in conjunction with antibodies to specific cell surface markers to determine receptor subtype expression in defined immune cell subpopulations using flow cytometry.
For Specific Aim 2, selective Type I and II receptor agonists and antagonists will be administered in vitro and in vivo and the immunologic effects of these agents on the following immune functions will be determined: T cell proliferation, II-2 secretion, T cell independent B cell proliferation, NK cell activity, monocyte II-1 secretion.
Specific Aim 3 will examine the relationship between receptor activation and the noted immune variables in a range of in vivo physiological conditions known to differ in steroid bioavailability. Effects of diurnal variation, sex, strain, and duration of endogenous corticosterone exposure will be evaluated. Finally, Specific Aim 4 will examine immune function in animals with downregulated adrenal steroid receptors secondary to chronic steroid exposure or aging. Taken together, these studies, which are a major component of the PI's RSDA, are designed to provide a foundation for understanding the role of neuroendocrine function in immune-related diseases such as AIDS.
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