Role of T Cell Mediated Immunity In Emotion And Stress Responsiveness

描述(申请人提供)：大量研究报告称，患有慢性炎症性疾病的人，包括过敏和自身免疫性疾病，与情绪反应增强和对压力的应对反应不良有关的精神并发症的发生率更高。包括抑郁和焦虑障碍在内的精神并发症给这些患者带来了巨大的负担，这也与炎症性条件下预后不良有关。人们对这种联系的原因知之甚少，也缺乏对潜在机制的研究。我们和我们的合作者的研究结果表明，在实验控制的条件下，表明情绪反应性增加的行为变化是外周淋巴细胞活动的结果，外周淋巴细胞负责炎症性疾病的启动和维持。然而，这些免疫细胞的活动是否与神经行为机制直接相关，或者是否与导致行为病理表现的其他神经免疫过程平行发展，仍存在重大争议。目前的应用将评估外周活化的T淋巴细胞是否必要并足以引发情绪行为变化。使用最先进的免疫学方法，通过使用缺乏成熟T淋巴细胞的RAG2/缺陷小鼠，我们计划评估通过过继转移体外分化的T细胞进行重建是否能够导致情绪行为改变和对心理应激源的反应不足。RAG2-/-小鼠将与从RAG2 D011.10转基因小鼠获得的体外分化的TH1或TH2细胞重组。这些小鼠表达针对卵清蛋白的T细胞抗原受体的转基因，因此这些动物确实含有OVA特异性T细胞。然后用OVA抗原攻击重组小鼠，并在开阔场地、高架迷宫、社会互动和蔗糖偏好测试中进行评估。对照组将由不同免疫方案下的幼稚RAG2-/-小鼠和未免疫(未激活)的重组RAG2-/-小鼠组成。基于我们最近对活化T细胞向脑内转运及其对细胞因子表达的影响的研究，我们将通过免疫组织化学和实时定量RT-PCR来研究它们在脑中的存在和细胞因子mRNA的表达。这些实验是在R21应用程序的框架内提出的，以测试不同重构策略下的行为差异是否可以量化。这些研究可能为进一步研究淋巴细胞对大脑功能和行为发挥特定作用的机制提供工作模型，并提供涉及免疫反应的适应性臂的神经免疫机制的有价值的信息。这可能会促进对身心互动的理解，并导致新的干预策略的发展，以改善慢性病患者的精神障碍的治疗。

DESCRIPTION (provided by applicant): A significant number of studies report that individuals suffering from chronic inflammatory diseases including allergic and autoimmune diseases have a higher incidence of psychiatric complications related to increased emotional reactivity and poor coping responses to stress. Such mental complications including depression and anxiety disorders impose a great burden to these patients which has been also related to the poor prognosis of the inflammatory condition. The reasons for this association are poorly understood and research on potential mechanisms is lacking. Results from our studies and those of our collaborator show that in experimentally controlled conditions, behavioral alterations indicative of increased emotional reactivity develop as a result of the activity of peripheral lymphocytes which are responsible for the initiation and maintenance of inflammatory diseases. There is however significant controversy if the activity of these immune cells is directly related with neurobehavioral mechanisms or if it is a phenomenon that develops in parallel with other neuroimmunological processes responsible for the manifestation of behavioral pathology. The present application will evaluate if activated T lymphocytes in the periphery are necessary and sufficient to induce emotional behavioral changes. Using state of the art methods in immunology by employing the RAG2-/- deficient mice which lacks mature T lymphocytes, we plan to assess if reconstitution by adoptive transfer of in vitro differentiated T cells is a condition capable of inducing altered emotional behavior and deficient responses to psychogenic stressors. RAG2-/- mice will be reconstituted with either in vitro differentiated TH1 or TH2 cells obtained from RAG2 D011.10 transgenic mice. These mice express the transgene for the T-cell antigen receptor that is specific for ovalbumin and therefore these animals do contain OVA specific T-cells. Groups of reconstituted mice will be then challenged with OVA antigen and evaluated in the open field, elevated plus maze, social interaction and sucrose preference tests. Control groups will consist of naive RAG2-/- mice under different immunization protocols and reconstituted RAG2-/- mice not immunized (not activated). Based on our recent studies about trafficking of activated T cells into the brain and their effects on cytokine expression, their presence in the brain will be studied by immunohistochemistry and cytokine mRNA expression by real-time RT-PCR. These experiments are proposed within the framework of an R21 application to test if differences on behavior under the different reconstitution strategies are quantifiable. These studies may provide a working model to further study the mechanisms by which lymphocytes exert specific effects on brain function and behavior and yield valuable information on neuroimmune mechanisms involving the adaptive arm of the immune response. This may advance the understanding of mind-body interaction and lead to the development of new strategies of interventions to improve the treatment of mental disorders in chronically ill patients.