Role of T Cell Mediated Immunity In Emotion And Stress Responsiveness

描述（由申请人提供）：大量研究报告称，患有慢性炎症性疾病（包括过敏性和自身免疫性疾病）的个体具有较高的精神并发症发生率，这些并发症与情绪反应性增加和应对压力反应不良有关。这些精神并发症包括抑郁症和焦虑症给这些患者带来了巨大的负担，这也与炎症性疾病的预后不良有关。这种关联的原因知之甚少，缺乏对潜在机制的研究。我们的研究结果和我们的合作者的研究结果表明，在实验控制条件下，由于外周淋巴细胞的活性，导致炎症性疾病的发生和维持，导致了表明情绪反应性增加的行为改变。然而，这些免疫细胞的活性是否与神经行为机制直接相关，或者它是否是一种与其他神经免疫过程平行发展的现象，这些神经免疫过程负责行为病理学的表现，这是一个重大的争议。本申请将评估外周中活化的T淋巴细胞是否是诱导情绪行为变化所必需和足够的。通过采用缺乏成熟T淋巴细胞的RAG 2-/-缺陷小鼠，使用免疫学中最先进的方法，我们计划评估通过体外分化T细胞的过继转移进行的重建是否是能够诱导改变的情绪行为和对心因性应激源的反应不足的状况。RAG 2-/-小鼠将用从RAG 2 D011.10转基因小鼠获得的体外分化的TH 1或TH 2细胞重建。这些小鼠表达对卵清蛋白特异的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抗原攻击重组小鼠组，并在旷场、高架十字迷宫、社会互动和蔗糖偏好试验中进行评价。对照组将由不同免疫方案下的幼稚RAG 2-/-小鼠和未免疫（未活化）的重建RAG 2-/-小鼠组成。基于我们最近关于活化T细胞向脑中的运输及其对细胞因子表达的影响的研究，将通过免疫组织化学和通过实时RT-PCR的细胞因子mRNA表达来研究它们在脑中的存在。在R21应用程序的框架内提出这些实验，以测试不同重构策略下的行为差异是否可量化。这些研究可能提供一个工作模型，以进一步研究淋巴细胞对脑功能和行为产生特定影响的机制，并产生有关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。 公共卫生相关性：包括过敏性和自身免疫性疾病在内的慢性炎症性疾病在美国非常普遍。研究表明，患有这些疾病的人患焦虑和抑郁症的发病率很高。然而，这种关系背后的机制知之甚少。目前的研究将评估是否分化的淋巴细胞的活动是负责外周炎症过程中的神经行为改变。拟议的实验结果可能会导致新的干预策略，以平衡慢性病患者的情绪。

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. PUBLIC HEALTH RELEVANCE: Chronic inflammatory diseases including allergic and autoimmune diseases are highly prevalent in the U.S. Studies have documented that individuals suffering from these conditions have a high incidence of anxiety and depressive disorders. However, the mechanisms underlying this relationship are poorly understood. The present studies will evaluate if the activity of differentiated lymphocytes are responsible for neurobehavioral alterations during peripheral inflammation. The results of the proposed experiments may lead to new strategies of intervention for balancing emotions in chronically ill patients.