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差异，而不是由抗原引起的内源性细胞因子作为动态细胞因子网络的一部分。因此，目前的项目研究大脑如何对T细胞细菌超级抗原（sag），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反应的自然免疫事件库的激活，但也影响适应性神经行为调整（例如，在疾病期间）。体内给予sag（如SEA和SEE）刺激T细胞产生高水平的肿瘤坏死因子-a （TNFa）。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）和著名的“抗应激”肽，痛觉肽/孤儿蛋白FQ （N/OFQ）的转录增加有关，行为变化显示出增加的新恐惧反应性（即对新奇事物的恐惧）。缺乏TNFa的动物对SEA的神经内分泌反应降低，大脑中的CRH拮抗剂可减轻味觉新恐惧症。这些数据暗示TNFa和CRH在T细胞超级抗原的神经和行为效应。基于这些观察结果，本提案将在SEA挑战的C57BIV6J小鼠中解决以下目标。Specific Aim 1将通过使用TNFa缺陷和TNFa受体I和/或II缺陷小鼠，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SEA激活T细胞后TNFa在脑内的潜在作用。在Specific Aim 2中，CRH在促进SEA行为效应中的作用将通过在终末纹、杏仁核和PVN的床核（已知介导CRH的焦虑和抗食欲作用的区域）特定部位给予CRH受体拮抗剂antalarmin来测试。最后，Specific Aim 3将探讨假设的抗焦虑肽N/OFQ在调节SEA挑战的行为效应中的调节作用。这些研究将利用缺乏N/OFQ或其受体ORL-1的小鼠。假设在边缘脑区域诱导N/OFQ有助于调节SEA刺激后诱导的焦虑过程（可能由CRH驱动）。这些研究将证实免疫激活是否会改变中枢神经系统对心理压力源的反应性，这反过来可能会促进人们了解内源性细胞因子（如TNFa）如何支持和/或影响对压力的行为适应。鉴于免疫系统在影响临床抑郁症动机系统改变中的作用日益受到重视，本研究将有助于了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.