Studies of interactions between the nervous and the immune systems have largely emphasized nervous system effects on the immune system. Effective interaction between the two systems requires two-way communication. This proposal focuses on the identification of messengers from the immune system that may signal immune responses to the central nervous system. Several studies have suggested that there are endocrine, electrophysiological and neurochemical changes in hypothalamic neurons during immune responses. In response to administration of Newcastle disease virus (NDV) or infection with influenza virus, we have shown elevations of plasma corticosterone, as well as increases in brain norepinephrine metabolism and the concentration of tryptophan. The cytokine, interleukin-1 (IL-1), is known to be produced by macrophages during immune challenges. IL-1 is considered to be an endogenous pyrogen and has behavioral effects. It activates the hypothalamic-pituitary- adrenal (HPA) axis, elevating circulating concentrations of CRF, ACTH and glucocorticoids. Peripherally administered IL-1 increases cerebral concentrations of MHPG, a major catabolite of norepinephrine, especially in the hypothalamus, and free tryptophan in all brain areas. Thus IL-1 administration mimics the responses observed following NDV administration or influenza virus infection and, therefore, is a good candidate for a messenger from the immune systems to the CNS. This proposal intends to characterize the neurochemical, endocrine and behavioral responses to administration of bacterial endotoxin, as well as viruses, and certain antigens, to determine the neurochemical and anatomical specificity. We will also test other cytokines (e.g., tumor necrosis factor, interferons) for their neurochemical and endocrine effects, and for their ability to enhance or attenuate the effects of IL- 1. We will attempt tot determine whether the effect of IL-1 on hypothalamic MHPG is direct or indirect, using intracerebral administration of IL-1, and with both central and peripheral administration of antagonists. A major aim is to determine whether IL-1 is the endogenous mediator of the endotoxin-induced endocrine and neurochemical changes. This will be attempted using certain peptide fragments of IL-1 considered to be antagonists and antisera to IL-1. If intracerebral IL-1 is effective, we may perform cannulation studies to attempt to determine the cerebral site of its action. The results of these studies may identify immune messengers to the CNS, and should thereby enhance our understanding of immune system communication with the nervous system. Although the studies proposed do not study HIV infection, we believe the resulting data will be relevant. AIDS victims frequently suffer neurological consequences, and it is very likely that these may be mediated by cytokines. Because the medical problems posed by the HIV virus are complex, any increased understanding of host resistance to disease is likely to benefit AIDS patients.
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