NEUROENDOCRINE EFFECTS ON HERPES SIMPLEX VIRUS IMMUNITY

人类和动物研究都有大量证据表明， 这表明免疫系统在功能上与两种免疫系统整合在一起。 中枢神经系统和内分泌系统。最近的实验证据 表明神经内分泌免疫轴在体内双向运作， 免疫系统接收并响应来自 神经和内分泌系统以及传递信号， 这些系统可以各自响应。因此，免疫反应受到 来指导神经内分泌调节。此外，一些研究表明， 人类和动物都已经证明，压力事件会在 在体液免疫和细胞免疫调节中具有重要作用。 然而，很少有研究集中在阐明的基本机制， 是压力诱导的免疫反应调节的基础， 解决特定病毒感染所必需的。 本提案的总体目标是使用已建立的小鼠模型 单纯疱疹病毒（HSV）感染的系统，以调查 应激相关神经内分泌相互作用的机制 免疫系统以及这些相互作用如何有助于 HSV感染的发病机制。这项研究的重点必然是 仅限于应激相关的皮质酮和肾上腺素释放 去甲肾上腺素直接释放到 淋巴组织通过直接交感神经支配。第一 这些研究的一个方面检查了这些药物对 激活HSV特异性记忆细胞毒性T淋巴细胞（CTLm）， 溶解性表型和改变的淋巴因子基因表达在 介导这些效应。调查这些问题的补充方法 神经内分泌对CTL增殖和功能的作用利用HSV- 特异性CTL细胞系。该建议的第二个方面扩展了这些 将体外研究转化为体内模型系统，以确定 束缚应激和相应的皮质酮释放， 肾上腺素和去甲肾上腺素对HSV特异性CTL杀伤能力的影响 在体内保护免受原发性和潜伏性HSV感染。最后，一个在 将采用体外方法研究这些神经内分泌作用， HSV抗原加工和呈递是HSV特异性 CTL激活。 防止HSV从潜伏状态再活化并限制 HSV感染复发的严重程度取决于 受感染宿主的免疫系统的能力。但 这种免疫调节最终导致HSV的潜在基础 发病机制还不清楚。总的来说，本报告中提出的研究 应用程序将提供洞察的作用和机制， 应激相关激素和神经肽调节抗病毒免疫 应对措施，并应有助于全面了解 压力、免疫功能和病毒发病机制之间的关系。

There is substantial evidence from both human and animal studies indicating that the immune system is functionally integrated with both the central nervous system and endocrine system. Recent experimental evidence suggests that the neuroendocrine-immune axis operates bi-directionally in that the immune system receives and responds to signals originating from the nervous and endocrine systems as well as delivering signals to which these systems can each respond. As a result, immune responses are subject to direct neuroendocrine regulation. In addition, a number of studies in both humans and animals have demonstrated that stressful events play a significant role in modulation of both humoral and cellular immunity. However, few studies have focused on elucidating the basic mechanisms that underlie stress-induced modulation of the immune response that is necessary for resolution of a specific virus infection. The overall aim of this proposal is to use an established murine model system of herpes simplex virus (HSV) infection to investigate the mechanisms underlying stress-associated neuroendocrine interactions with the immune system and how these interactions may contribute to the pathogenesis of HSV infection. The focus of this study is necessarily limited to the stress-associated release of corticosterone and epinephrine from the adrenal gland and norepinephrine which is released directly into lymphoid tissues via direct sympathetic neural innervation. The first aspect of these studies examines the effect of these agents on the activation of HSV-specific memory cytotoxic T lymphocytes (CTLm) to the lytic phenotype and the role that an altered lymphokine gene expression in mediating these effects. A complementary approach to investigate these neuroendocrine effects on CTL proliferation and function utilizes an HSV- specific CTL cell line. The second aspect of this proposal extends these in vitro studies to an in vivo model system to determine the effect of restraint stress and the corresponding release of corticosterone, epinephrine and norepinephrine on the ability of HSV-specific CTL to protect against primary and latent HSV infection in vivo. Last, an in vitro approach will be undertaken to study these neuroendocrine effects on HSV antigen processing and presentation that is necessary for HSV-specific CTL activation. The ability to prevent HSV reactivation from the latent state and to limit the severity of recurrent episodes of HSV infection is dependent upon the competence of the immune system of the infected host. However, the underlying basis for such immune modulation culminating in HSV pathogenesis is not understood well. Overall, the studies proposed in this application will provide insight into the role of and mechanisms by which stress-related hormones and neuropeptides modulate anti-viral immune responses and should contribute significantly to the overall understanding of the relationship among stress, immune function, and viral pathogenesis.