CYTOKINES AND HYPOTHALAMIC-PITUITARY-IMMUNE INTERACTIONS

描述(改编自申请人的摘要)：长期 这个应用程序的目标是了解免疫和 神经内分泌系统在被压力或感染激活时相互作用 人类和非人类灵长类动物。具体目标将集中在 炎性细胞因子(IL-1、IL-6、TNFα)及其作用机制 下丘脑-垂体-肾上腺(HPA)的激活及其作用 性腺类固醇在调节细胞因子和神经内分泌反应中的作用。 此前在研究人员实验室进行的研究已经证实 脑室注射IL-1对猴HPA轴的刺激作用 这种影响可以被促肾上腺皮质激素释放激素(CRH)阻断 对抗性。对猴子的初步研究表明，ICV IL-1也 导致淋巴细胞功能的严重抑制和显著的刺激 IL-6分泌到外周血中，可能是通过CRH依赖机制。 在本应用中，使用恒河猴，IL-1 CRH在 大脑和性腺类固醇对它们的调节将在体内进行检查 关于HPA激活和调节外周血细胞的机制 淋巴细胞和细胞因子反应。一个主要的焦点将是描述 A细胞因子和神经内分泌反应的研究进展 人类的生理性炎症挑战。低剂量的高剂量 纯化的内毒素制剂将用于刺激细胞因子的释放和 研究女性在有无HPA的情况下的反应特征 性腺类固醇。脑脊液刺激后中枢细胞因子和促肾上腺皮质激素释放激素的变化 将在使用慢性脑脊液导管的猴子身上检测内毒素，并 将特定的细胞因子拮抗剂注入脑室以建立作用 脑内内源性细胞因子在神经内分泌调节中的作用这个 性腺类固醇调节中枢细胞因子释放的能力也将 被研究。这些研究可能涉及广泛的人类疾病。 由于由损伤或感染引发脑内细胞因子相互作用可能是 与神经退行性变和免疫抑制有关。如果性激素 抑制这些细胞因子-神经肽的相互作用，这样的病理可能是 当性类固醇水平下降时，情况会加剧。因此，这些研究应该有 与性激素替代这一重要的临床问题直接相关 在更年期和其他性腺功能低下的状态下。

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term objective of this application is to understand how the immune and neuroendocrine systems interact when activated by stress or infection in the human and nonhuman primate. The specific aims will focus on the inflammatory cytokines (IL-1, IL-6, TNFalpha) and mechanisms of hypothalamic-pituitary-adrenal (HPA) activation with an emphasis in the role of gonadal steroids in modulating cytokine and neuroendocrine responses. Previous studies in the investigators' laboratory have established that intracerebroventricular (icv) IL-1 stimulates the HPA axis in the monkey and that this affect can be blocked by corticotropin-releasing hormone (CRH) antagonism. Preliminary studies in the monkey indicate that icv IL-1 also causes profound suppression of lymphocyte function and marked stimulation of Il-6 secretion into peripheral blood, possibly by a CRH dependent mechanism. In this application, using rhesus monkeys, IL-1 CRH interactions in the brain and their modulation by gonadal steroids will be examined in vivo with respect to mechanisms of HPA activation and regulation of peripheral lymphocyte and cytokine responses. A major focus will be to characterize the endogenous cytokine and neuroendocrine responses caused by a physiological inflammatory challenge in the human. Low doses of a highly purified endotoxin preparation will be use to stimulate cytokine release and to characterize the HPA response in women in the presence and absence of gonadal steroids. The CNS cytokines and CRH into CSF after stimulation with endotoxin will be measured in monkeys with chronic CSF catheters, and specific cytokine antagonists will be infused icv to establish a role for the endogenous cytokines within the brain in neuroendocrine regulation. The ability of gonadal steroids to modulate central cytokine release will also be studied. These studies may relate to a wide range of human diseases since cytokine interactions in brain triggered by injury or infection may be associated with neurodegeneration and immunosuppression. If sex steroids restrain these cytokine-neuropeptide interactions, such pathology could be exacerbated when sex steroid levels fall. These studies should thus have direct relevance to the important clinical issue of sex steroid replacement during menopause and in other hypogonadal states.