CYTOKINE MEDIATION OF IMMUNE ACTIVATION OF THE CNS

对神经系统和免疫系统之间相互作用的研究 主要强调神经系统对免疫系统的影响。有效 两个系统之间的交互需要双向通信。这 该提案的重点是识别免疫系统的信使， 免疫系统可能向中枢神经系统发出免疫反应信号。 一些研究表明，有内分泌， 下丘脑神经元的电生理和神经化学变化 在免疫反应中。为了回应纽卡斯尔的管理 疾病病毒（NDV）或流感病毒感染，我们已经表明， 血浆皮质酮升高，以及脑内 去甲肾上腺素代谢和色氨酸浓度。的 已知细胞因子白细胞介素-1（IL-1）由巨噬细胞产生 在免疫挑战中。IL-1被认为是一种内源性热原 并且具有行为效应。它会激活下丘脑-垂体- 肾上腺（HPA）轴，升高CRF，ACTH和 糖皮质激素外周注射IL-1可增加大脑功能 浓度的MHPG，去甲肾上腺素的主要分解代谢物，特别是 在下丘脑和游离色氨酸在所有的大脑区域。因此IL-1 给药模拟NDV给药后观察到的应答 或流感病毒感染，因此，是一个很好的候选人， 从免疫系统到中枢神经系统的信使。 该提案旨在描述神经化学，内分泌和 对细菌内毒素给药的行为反应，以及 病毒和某些抗原，以确定神经化学和 解剖特异性我们还将测试其他细胞因子（例如，肿瘤 坏死因子，干扰素），用于其神经化学和内分泌 作用，以及它们增强或减弱IL-12的作用的能力。 1.我们将试图确定IL-1对 下丘脑MHPG是直接或间接的，使用脑内 IL-1的施用，以及中枢和外周 拮抗剂的施用。主要目的是确定IL-1是否 是内毒素诱导的内分泌的内源性介质， 神经化学变化这将尝试使用某些肽 IL-1的片段被认为是IL-1的拮抗剂和抗血清。如果 脑内IL-1是有效的，我们可以进行插管研究， 试图确定其作用的大脑部位。 这些研究的结果可能会确定免疫信使的中枢神经系统， 从而增强我们对免疫系统的理解 与神经系统的沟通。尽管这些研究建议 如果不研究艾滋病毒感染，我们相信由此产生的数据将是相关的。 艾滋病患者经常遭受神经系统的后果，这是非常重要的。 这可能是由细胞因子介导的。因为医疗 艾滋病毒引起的问题是复杂的，任何增加的了解 宿主对疾病的抵抗力可能会使艾滋病患者受益。

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.