CYTOKINE MEDIATION OF IMMUNE ACTIVATION OF THE CNS

细胞因子介导中枢神经系统免疫激活

• 批准号: 2750936
• 负责人: Adrian John Dunn
• 金额: $ 21.56万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-30 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750936
• 关键词: ACTH inhibitor; Newcastle disease virus; adrenergic receptor; adrenocorticotropic hormone; aldosterone; bacterial polysaccharides; behavior; catecholamines; central nervous system neoplasms; central nervous system stimulants; corticosterone; cytokine; endotoxins; host organism interaction; interleukin 1; laboratory mouse; leukocyte activation /transformation; neurochemistry; neurotransmitter metabolism; neurotransmitters; norepinephrine; psychoneuroimmunology; stimulant /agonist; tumor necrosis factor alpha; virus antigen

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.

神经和免疫系统之间的相互作用的研究具有 在很大程度上强调了神经系统对免疫系统的影响。有效的 两个系统之间的相互作用需要双向通信。这 提案重点是从免疫中确定使者 可能对中枢神经系统产生免疫反应的系统。 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 在免疫反应期间。回应纽卡斯尔的管理 疾病病毒（NDV）或流感病毒感染，我们已经显示 血浆皮质酮的升高以及大脑的增加 去甲肾上腺素代谢和色氨酸的浓度。这 已知细胞因子，白介素1（IL-1）是由巨噬细胞产生的 在免疫挑战期间。 IL-1被认为是内源性热原 并具有行为影响。它激活下丘脑 - 垂体 - 肾上腺（HPA）轴，CRF，ACTH和ACTH和 糖皮质激素。外围施用的IL-1增加脑增加 MHPG的浓度，一种主要的去甲肾上腺素的分解代谢物，尤其是 在下丘脑中，在所有大脑区域中游离色氨酸。因此IL-1 管理模仿NDV给药后观察到的响应 或流感病毒感染，因此是 从免疫系统到中枢神经系统的使者。 该建议旨在表征神经化学，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 解剖学特异性。我们还将测试其他细胞因子（例如肿瘤 坏死因子，干扰素）用于神经化学和内分泌 效果，以及它们增强或衰减IL的影响的能力 1。我们将尝试确定IL-1对 下丘脑MHPG是直接或间接的，使用脑内 给药IL-1，并且中央和周围 拮抗剂的管理。一个主要目的是确定IL-1是否 是内毒素诱导的内分泌和 神经化学变化。这将尝试使用某些肽 IL-1的片段被认为是拮抗剂和对IL-1的抗血清。如果 脑内IL-1是有效的，我们可能会进行插管研究 尝试确定其作用的大脑部位。 这些研究的结果可能会发现中枢神经系统的免疫使者 因此，应该增强我们对免疫系统的理解 与神经系统的沟通。尽管拟议的研究确实 不研究艾滋病毒感染，我们认为由此产生的数据将是相关的。 艾滋病受害者经常遭受神经系统后果，这是非常 这些可能是由细胞因子介导的。因为医疗 艾滋病毒病毒带来的问题很复杂，有任何增加的理解 宿主对疾病的抵抗可能使艾滋病患者受益。