CYTOKINE EFFECTS ON THE CENTRAL NERVOUS SYSTEM

对神经和免疫系统之间相互作用的研究已经 主要强调神经系统对免疫系统的影响。有效 这两个系统之间的互动需要双向交流。这 提案的重点是识别来自免疫系统的信使 可能向中枢神经系统发出免疫反应信号的系统。 几项研究表明，有内分泌， 下丘脑神经元的电生理和神经化学变化 在免疫反应过程中。对纽卡斯尔政府的回应 疾病病毒(NDV)或感染流感病毒，我们已经表明 血浆皮质酮升高和脑内皮质酮升高 去甲肾上腺素代谢和色氨酸浓度。这个 已知的细胞因子，白介素1(IL-1)由巨噬细胞产生 在免疫挑战期间。IL-1被认为是一种内源性热原 并对行为产生影响。它激活了下丘脑--脑下垂体-- 肾上腺(HPA)轴，升高循环CRF、ACTH和 糖皮质激素。外周给药IL-1增加大脑 去甲肾上腺素的主要分解代谢物MHPG的浓度，尤其是 在下丘脑，在所有大脑区域都有游离色氨酸。因此，IL-1 管理模仿新城疫病毒管理后观察到的反应 或流感病毒感染，因此是一个很好的候选者 从免疫系统到中枢神经系统的信使。 这项建议旨在描述神经化学、内分泌和 对注射细菌内毒素的行为反应，以及 病毒和某些抗原，以确定神经化学和 解剖学上的特异性。我们还将测试其他细胞因子(例如，肿瘤 干扰素)对其神经化学和内分泌的影响 作用，以及增强或减弱IL-2影响的能力。 1.我们将尝试确定IL-1是否对 下丘脑MHPG是直接或间接的，使用脑内 IL-1的给药，以及中枢和外周的 给药的拮抗剂。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。这将尝试使用某些多肽 被认为是IL-1拮抗剂和抗血清的IL-1片段。如果 脑内IL-1有效，我们可能会进行插管研究 试图确定其活动的大脑部位。 这些研究的结果可能确定中枢神经系统的免疫信使， 因此应该会增强我们对免疫系统的了解 与神经系统的沟通。尽管所提议的研究 不研究艾滋病毒感染，我们相信结果数据将是相关的。 艾滋病患者经常遭受神经后果，而且非常 这些可能是由细胞因子介导的。因为医疗队 艾滋病毒带来的问题是复杂的，任何增加的理解 宿主对疾病的抵抗力很可能使艾滋病患者受益。

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.