Neural and Behavioral Impact of T Cell Activation

描述（由申请人提供）：细胞因子免疫治疗可能导致神经精神问题。 这可能反映了大脑对外源性细胞因子的反应方式与作为动态细胞因子网络一部分的抗原引起的内源性细胞因子的反应方式的差异。 因此，目前的项目解决了大脑如何对T细胞细菌超抗原（SAgs），特别是葡萄球菌肠毒素A（SEA）诱导的内源性细胞因子产生反应。 该模型涉及调节免疫应答的免疫事件的天然库的激活，但也影响适应性神经行为调节（例如，生病期间）。 SAg的施用（例如，SEA和SEE）在体内刺激T细胞产生高水平的肿瘤坏死因子-α（TNF α）。 这与杏仁核和下丘脑室旁核中中枢促肾上腺皮质激素释放激素（CRH）和公认的“抗应激”肽（N/OFQ）的转录增加有关，行为变化显示出增加的恐新反应性（即害怕新奇）。 TNFa缺乏的动物显示对SEA的神经内分泌反应降低，并且脑中的CRH拮抗作用减弱味觉新恐怖症。 这些数据暗示TNFa和CRH在T细胞超抗原的神经和行为效应中。 基于这些观察结果，本提案将在SEA攻毒的C57 BIV 6 J小鼠中实现以下目标。 具体目标1将通过使用TNF α缺陷型和TNF α受体I和/或II缺陷型小鼠，进一步表征内源性TNF α在SEA的神经和行为效应中的作用。 这些研究还将解决用SEA活化T细胞后TNF α作用在脑内的潜在作用。 在具体目标2中，CRH在促进SEA的行为效应中的作用将通过CRH受体拮抗剂antalarmin向终纹、杏仁核和PVN的床核（已知介导CRH的致焦虑和抗食欲效应的区域）的位点特异性施用来测试。 最后，具体目标3将解决的调节作用，假设的抗焦虑肽，N/OFQ，在调节行为的影响，SEA的挑战。 这些研究将利用缺乏N/OFQ或其受体ORL-1的小鼠。 假设在边缘脑区域中诱导N/OFQ用于调节SEA激发后诱导的致焦虑过程（可能由CRH驱动）。 这些研究将证实免疫激活是否改变CNS对心理应激源的反应性，这反过来可能促进了解内源性细胞因子（如TNF α）如何支持和/或影响对应激的行为适应的努力。 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越来越受到重视，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.