Neural and Behavioral Impact of T Cell Activation

描述(由申请者提供)：细胞因子免疫治疗可导致神经精神问题。这可能反映了大脑对外源性细胞因子的反应方式的不同，而不是作为动态细胞因子网络的一部分的抗原引发的内源性细胞因子。因此，目前的项目解决了大脑如何对T细胞细菌超抗原(SAG)，特别是金黄色葡萄球菌肠毒素A(SEA)诱导的内源性细胞因子的产生做出反应。这一模型包括激活一系列免疫事件，这些免疫事件调节免疫反应，但也影响适应性神经行为调整(例如，在疾病期间)。体内给予SAGS(如SEA和SEE)可刺激T细胞产生高水平的肿瘤坏死因子-α(TNFa)。这与中枢促肾上腺皮质激素释放激素(CRH)和杏仁核、下丘脑室旁核中著名的“抗应激”肽、伤害素/孤啡肽FQ(N/OFQ)的转录增加有关，行为变化显示出新的恐惧症反应增加(即害怕新奇)。缺乏TNFa的动物表现出对SEA的神经内分泌反应减少，大脑中CRH的拮抗作用减轻了味觉新恐惧症。这些数据表明，TNFa和CRH参与了T细胞超抗原对神经和行为的影响。基于这些观察，这项建议将解决以下目标C57BIV6J小鼠挑战SEA。具体目标1将通过使用TNFa缺陷和TNFa受体I和/或II缺陷的小鼠，进一步表征内源性TNFa在SEA的神经和行为效应中的作用。这些研究还将探讨在SEA激活T细胞后，TNFa在大脑中的潜在作用。在特定目的2中，CRH在促进SEA行为效应中的作用将通过将CRH受体拮抗剂antalarmin特异性地注射到终纹、杏仁核和PVN的床核来测试，这些区域是CRH引起焦虑和抑制食欲的区域。最后，具体目标3将阐述假设的抗焦虑多肽N/OFQ在调节海洋挑战的行为效应中的调节作用。这些研究将利用N/OFQ或其受体ORL-1缺乏的小鼠。有人假设，边缘脑区N/OFQ的诱导有助于调节SEA攻击后诱导的焦虑过程(可能是由CRH驱动的)。这些研究将证实免疫激活是否改变了中枢神经系统对心理应激源的反应性，这反过来可能促进理解内源性细胞因子(如TNFa)如何支持和/或影响对应激的行为适应。鉴于免疫系统在影响临床抑郁症中改变的动机系统中的作用日益受到重视，本研究将有助于理解情感性疾病的病因和治疗策略。

DESCRIPTION (provided by applicant): Neuropsychiatric problems can result from cytokine immunotherapy. This may reflect differences in the way the brain responds to exogenous cytokines as opposed to endogenous cytokines elicited by antigens as part of a dynamic cytokine network. Therefore, the current project addresses how the brain reacts to endogenous cytokine production induced by T cell bacterial superantigens (SAgs), and in particular Staphyloccocal Enterotoxin A (SEA). This model involves activation of a natural repertoire of immunological events that regulate immune responses, but also influence adaptive neurobehavioral adjustments (e.g., during sickness). Administration of SAgs (e.g., SEA and SEE) in vivo stimulates T cells to produce high levels of tumor necrosis factor-a (TNFa). This has been associated with increased transcription of central corticotropin releasing hormone (CRH) and the reputed "anti-stress" peptide, nociceptin/orphanin FQ (N/OFQ) in the amygdala, and paraventricular nucleus of the hypothalamus, with behavioral changes showing increased neophobic reactivity (i.e. fear of novelty). Animals deficient in TNFa display reduced neuroendocrine responses to SEA, and CRH antagonism in the brain attenuates gustatory neophobia. These data implicate TNFa and CRH in the neural and behavioral effects of T cell superantigens. Based on these observations, this proposal will address the following aims in C57BIV6J mice challenged with SEA. Specific Aim 1 will characterize further the role of endogenous TNFa in the neural and behavioral effects of SEA, through the use of TNFa deficient and TNFa receptor I and/or II deficient mice. These studies will also address the potential role of TNFa actions within the brain after T cell activation with SEA. In Specific Aim 2 the role of CRH in promoting the behavioral effects of SEA will be tested by site-specific administration of CRH receptor antagonist, antalarmin, into the bed nucleus of the stria terminalis, amygdala and PVN, regions known to mediate anxiogenic and anti-appetitive effects of CRH. Finally, Specific Aim 3 will address the modulatory role of the hypothesized anxiolytic peptide, N/OFQ, in regulating the behavioral effects of SEA challenge. These studies will utilize mice deficient for N/OFQ or its receptor, ORL-1. It is hypothesized that the induction of N/OFQ in limbic brain regions serves to modulate anxiogenic processes (perhaps driven by CRH) that are induced after challenge with SEA. These studies will confirm if immunological activation modifies CNS reactivity to psychological stressors, which in turn may promote efforts to understand how endogenous cytokines (such as TNFa) support and/or influence behavioral adaptation to stress. In view of the increasing emphasis on the role of the immune system in affecting motivational systems altered in clinical depression, this research will contribute to understanding the aetiology and strategies for treatment of affective illness.