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: 8265622
• 负责人: Leonardo H Tonelli
• 金额: $ 18.75万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265622
• 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.

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对压力的应对反应较差有关。包括抑郁症和焦虑症在内的精神并发症给这些患者带来了巨大的负担，这也与炎症性疾病的不良预后有关。人们对这种关联的原因知之甚少，也缺乏对潜在机制的研究。我们和我们合作者的研究结果表明，在实验控制的条件下，由于外周淋巴细胞的活动而导致情绪反应性增加的行为改变，而外周淋巴细胞负责炎症疾病的引发和维持。然而，如果这些免疫细胞的活性与神经行为机制直接相关，或者它是否是与导致行为病理学表现的其他神经免疫过程并行发展的现象，则存在重大争议。本申请将评估外周激活的T淋巴细胞是否必要且足以诱导情绪行为变化。通过使用缺乏成熟T淋巴细胞的RAG2-/-缺陷小鼠，我们计划利用免疫学中最先进的方法来评估通过体外分化T细胞的过继转移进行重建是否是一种能够诱导情绪行为改变和对心因性应激源反应不足的条件。 RAG2-/-小鼠将用从RAG2 D011.10转基因小鼠获得的体外分化的TH1或TH2细胞进行重建。这些小鼠表达卵清蛋白特异性 T 细胞抗原受体转基因，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、社交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初始RAG2-/-小鼠和未免疫（未激活）的重组RAG2-/-小鼠组成。根据我们最近关于活化 T 细胞进入大脑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实时 RT-PCR 的细胞因子 mRNA 表达来研究它们在大脑中的存在。这些实验是在 R21 应用程序的框架内提出的，旨在测试不同重构策略下的行为差异是否可以量化。这些研究可能提供一个工作模型来进一步研究淋巴细胞对大脑功能和行为产生特定影响的机制，并产生涉及免疫反应适应性臂的神经免疫机制的有价值的信息。这可能会增进对身心相互作用的理解，并导致开发新的干预策略，以改善慢性病患者精神障碍的治疗。

项目成果

Dissociation between sickness behavior and emotionality during lipopolysaccharide challenge in lymphocyte deficient Rag2(-/-) mice.

• DOI: 10.1016/j.bbr.2014.09.030
• 发表时间: 2015-02-01
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Clark, Sarah M.;Michael, Kerry C.;Klaus, Joseph;Mert, Abdullah;Romano-Verthelyi, Ari;Sand, Joseph;Tonelli, Leonardo H.
• 通讯作者: Tonelli, Leonardo H.