The immune system plays a pivotal role in cancer, autoimmune disorders and infectious diseases such as AIDS. Numerous studies have demonstrated that stress is associated with alterations in measures of the immune response, thereby providing support for he existence of a neuro-immune axis which may be relevant to the pathogenesis and treatment of these conditions. Nevertheless, the mechanisms of the effect of stress on the immune system are in need of further elucidation. For example, in terms of immunologic mechanisms, the contribution of changes in cell function versus changes in cell composition of the tissue studied remains uncertain. Furthermore, although stress-related alterations in neuroendocrine hormones have been well characterized and receptors for these hormones on immune cells have been described, the role of the neuroendocrine system in the regulation of the immune response during stress is unclear. The long-term objectives of the proposed research are to further elucidate the neuroendocrine and immunologic mechanisms of stress-related alterations in immune measures. To study these neuroendocrine-immune mechanisms, the applicant has developed an animal stress model which reliably alters neuroendocrine and immune variables by exposing rats to 5 minutes of restraint.
Specific Aim 1 of the proposed project is to further characterize and investigate these restraint-induced immune alterations by measuring immune cell composition and immune cell function in the spleen, mesenteric lymph nodes and peripheral blood. Immune cell composition including the numbers of total T cells, T suppressor cells, T helper cells, B cells, NK cells and monocyte/macrophages will be determined by flow cytometry, and immune cell function will be determined by assays of lymphocyte activation, lymphokine production, lymphokine receptor expression and activation, and NK cell activity.
Specific Aim 2 is to determine the role of hormones secreted by the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) in the restraint-induced immune alterations. To accomplish this aim, corticotropin releasing factor (CRF) will be immunoneutralized by injecting the rats with an anti CRF antibody 90 minutes prior to restraint exposure. CRF is a pivotal molecule in the HPA response to stress and is a major stimulus for the HPA derived hormones; ACTH, beta-endorphin and corticosterone. In separate experiments, chlorisondamine chloride, the ganglionic blocking agent, and Timolol, a peripheral beta receptor antagonist, will be injected 90 minutes prior to restraint in order to block the influence of catecholamines released by ANS activation. The proposed research will contribute to basic knowledge about the effect of stress on the immune system and may provide data critical to our understanding of the role of the neuro-immune axis in HIV infection and AIDS.
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