Role of T Cell Mediated Immunity In Emotion And Stress Responsiveness

T 细胞介导的免疫在情绪和压力反应中的作用

• 批准号: 8113052
• 负责人: Leonardo H Tonelli
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113052
• 关键词: Address; Adoptive Transfer; Affect; Allergic Disease; Allergic rhinitis; Anhedonia; Animal Model; Animals; Antigen Receptors; Antigens; Anxiety; Anxiety Disorders; Atopic Dermatitis; Autoimmune Diseases; B-Lymphocytes; Behavior; Behavioral; Brain; Brain region; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Chronic; Chronically Ill; Clinical Research; Complex; Control Groups; Depressive disorder; Development; Disease; Emotional; Emotions; Endocrine system; Epidemiologic Studies; Equilibrium; Etiology; Extrinsic asthma; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunization; Immunohistochemistry; Immunology; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-2; Interleukin-6; Intervention; Knowledge; Laboratories; Lead; Lymphocyte; Maintenance; Mature T-Lymphocyte; Mediating; Mental Depression; Mental disorders; Methods; Modeling; Mood Disorders; Multiple Sclerosis; Mus; Neuroimmunomodulation; Neurotransmitters; Ovalbumin; Pathology; Patients; Pattern; Peripheral; Play; Process; Production; Protocols documentation; Psoriasis; Psyche structure; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Role; Social Interaction; Stress; Sucrose; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Time; Tissues; Transgenes; Transgenic Mice; Work; arm; base; behavior influence; behavior test; coping; cytokine; depressive symptoms; improved; mRNA Expression; mind body interaction; neurobehavioral; outcome forecast; preference; reconstitution; research study; response; stressor; trafficking

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.

描述（由申请人提供）：大量研究报告说，患有慢性炎症性疾病（包括过敏和自身免疫性疾病）的人的精神病并发症发生率更高，与情绪反应增加以及对压力的应对反应不佳有关。包括抑郁症和焦虑症在内的精神并发症对这些患者造成了很大的负担，这也与炎症疾病的预后不良有关。这种关联的原因知之甚少，并且缺乏对潜在机制的研究。我们的研究和合作者的结果表明，在实验控制的条件下，行为改变，表明由于周围淋巴细胞的活性而导致情绪反应性提高，这些活动导致炎症性疾病的引发和维持。但是，如果这些免疫细胞的活性与神经行为机制直接相关，或者是一种与其他导致行为病理表现的现象相关的现象，则存在重大争议。本应用将评估外围活化的T淋巴细胞是否必要且足以诱导情绪行为变化。通过采用缺乏成熟T淋巴细胞的RAG2 - / - 缺陷小鼠，使用ART方法在免疫学中使用，我们计划评估是否通过在体外分化的T细胞的过继转移来进行重构是一种能够诱导情绪行为改变的疾病，并且对心理源性压力的反应不足。 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细胞重构。这些小鼠表达针对卵蛋白特异的T细胞抗原受体的转基因，因此这些动物确实包含卵子特异性的T细胞。然后，将通过OVA抗原挑战一组重构小鼠，并在空旷的地方进行评估，升高的迷宫，社交互动和蔗糖偏好测试。对照组将由不同的免疫协议下的幼稚rag2 - / - 小鼠组成，并重新结构的RAG2 - / - 小鼠未经免疫（未激活）。基于我们最近关于将活化T细胞运输到大脑及其对细胞因子表达的影响的研究，将通过实时RT-PCR通过免疫组织化学和细胞因子mRNA表达来研究它们在大脑中的存在。这些实验是在R21应用程序框架内提出的，以测试是否可以量化不同的重组策略下的行为差异。这些研究可以提供一个工作模型，以进一步研究淋巴细胞对脑功能和行为发挥特定影响的机制，并就涉及免疫反应适应性臂的神经免疫机制产生有价值的信息。这可能会提高人们对思维体相互作用的理解，并导致开发新的干预策略，以改善长期患者的精神障碍治疗。 公共卫生相关性：包括过敏和自身免疫性疾病在内的慢性炎症性疾病在美国的研究中很普遍，已经证明患有这些病症的人患有焦虑和抑郁症的人很高。但是，这种关系的基础机制知之甚少。本研究将评估分化淋巴细胞的活性是否导致周围炎症期间神经行为改变。拟议的实验的结果可能会导致新的干预策略，以平衡慢性病患者的情绪。