The long term objectives of the proposed research are to further understand the role of adrenal steroids in the regulation of specific immune responses and the development of diseases involving the immune system, including AIDS. Over the past five years the applicant has established that the expression and activation of the receptors for adrenal steroids are critical determinants of steroid action on the immune response. To apply this basic understanding of adrenal steroid receptor physiology to a disease model, the applicant proposes to investigate adrenal steroid-immune interactions in animals infected with lymphocytic choriomeningitis virus (LCMV), and RNA virus primarily cleared by virus-specific cytotoxic T lymphocytes (CTLs). These studies are based on the applicants interesting preliminary data which suggests that during LCMV infection there is increased adrenal steroid secretion which is accompanied by evidence of adrenal steroid receptor activation in relevant immune tissues at the time when CTL activity is peaking. Since adrenal steroids are typically immunosuppressive, these results suggest that adrenal steroids may be involved in feedback inhibition of the CTL response to LCMV. To develop his skills in viral immunolology and to further his long term research objectives, the applicant plans to investigate the role of adrenal steroids in CTL regulation during LCMV infection. These studies will be conducted in close collaboration with a well-established viral immunologist. The proposed research plan will determine 1) whether adrenal steroids are elevated during LCMV infection and when (Specific Aim 1), 2) whether increases in adrenal steroids are associated with activation of the receptors for adrenal steroids in relevant immune cells and tissues (Specific Aims 2,3, and 4), 3) whether adrenal steroid receptors activation is associated with decreases in specific immune functions relevant to CTL activity (Specific Aim 5), and 4) if removal or administration of the naturally occurring adrenal steroid, corticosterone, respectively enhances or inhibits specific immune functions which are relevant to CTL activity and viral replication (Specific Aim 6) The applicant also proposes to follow-up on interesting data from the previous project period which suggests that type II adrenal steroid receptor expression may play an important role in adrenal steroid-induced cell death, or apoptosis, in immature T cells. Knowledge gained from these new investigations may provide the foundation for the use of neuroendocrine manipulations at the hormone or receptor level to prevent or treat diseases associated with the immune system.
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|Ruzek, M C; Miller, A H; Opal, S M et al. (1997) Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection. J Exp Med 185:1185-92|