Aids exerts its ultimate pathological and lethal effects through immunosuppression. This project investigates a newly-discovered mediator of immunosuppression -- the action of the Interleukin-1 (IL-1) in the brain. Recent studies in our laboratory have found that both infusion of very low doses of exogenous IL-1 into the brain (3.1 to 12.5 x 10 15 moles) and stimulation of endogenous IL-1 release in brain markedly suppresses various cellular immune responses, including Natural Killer Cell activity, response of lymphocytes to mitogen, and Interleukin-2 (IL- 2) production. This suppression of cellular immune responses by IL-1 in brain (hereafter referred to as """"""""brain IL-1 induced immunosuppression"""""""") is blocked by infusion into the brain of low doses of alpha-melanocyte stimulating hormone (a-MSH) a substance known to block the biological action of IL-1. Studies are proposed to investigate the responses produced by IL-1 in brain that lead to immunosuppression. IL-1 is a powerful activator of pituitary-adrenal activity; however, preliminary data makes clear that IL-1 in brain suppresses cellular immune responses by activating neural pathways as well as stimulating release of immunosuppressive hormones. Studies will examine the likelihood that IL-1 in brain activates autonomic pathways to peripheral immune organs, such as spleen, which contributed to immunosuppression. Norepinephrine turnover is measured in spleen as well as elevation of peripheral catecholamines in blood (epinephrine and norepinephrine). Studies will determine whether IL-1 in brain concurrently activates autonomically-mediated responses (heart-rate and blood pressure change). Further, studies determine whether blocking of peripheral autonomic activation (by pharmacological ganglionic blockage) will prevent brain IL-1-inducted immunosuppression. Also, the role of corticotrophin releasing factor (CRF), which not only mediates pituitary-adrenal activity but also can produce autonomic activation, is assessed by blocking (immunoneutralizing) CRF in brain prior to IL-1 infusion. In addition, the possibility that prostaglandins mediate brain IL-1 inducted immunosuppression is examined. Finally, studies are proposed to determine what immune-related cells are affected by IL-1 acting in the brain.
| Quan, N; Sundar, S K; Weiss, J M (1994) Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol 49:125-34 |
| Sundar, S K; Cierpial, M A; Kamaraju, L S et al. (1991) Human immunodeficiency virus glycoprotein (gp120) infused into rat brain induces interleukin 1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses. Proc Natl Acad Sci U S A 88:11246-50 |
| Weiss, J M; Sundar, S K; Cierpial, M A et al. (1991) Effects of interleukin-1 infused into brain are antagonized by alpha-MSH in a dose-dependent manner. Eur J Pharmacol 192:177-9 |
| Sundar, S K; Cierpial, M A; Kilts, C et al. (1990) Brain IL-1-induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system by corticotropin-releasing factor. J Neurosci 10:3701-6 |
