A translational model of neuro-immune therapy for PTSD in veterans of the OEF/OIF

OEF/OIF 退伍军人 PTSD 神经免疫治疗的转化模型

• 批准号: 8143156
• 负责人: Leonardo H Tonelli
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143156
• 关键词: Acute; Adoptive Transfer; Affect; Afghanistan; Agreement; Animal Model; Animals; Anxiety; Anxiety Disorders; B-Lymphocytes; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Model; Biological; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRH gene; Cell physiology; Cells; Confocal Microscopy; Corticosterone; Development; Disease; Drug Formulations; Effectiveness; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exposure to; Extinction (Psychology); Flow Cytometry; Freedom; Fright; Gender; Hormonal; Immune response; Immune system; Immunohistochemistry; Immunotherapy; In Vitro; Inbred BALB C Mice; Incidence; Inflammatory; Inflammatory Response; Intervention; Iraq; Laboratories; Lymphocyte; Lymphokines; Mediating; Mental Depression; Mental disorders; Modeling; Mood Disorders; Mus; Odors; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Plasma; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Process; Production; Psychoneuroimmunology; Reproducibility; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Services; Sleep Disorders; Sleeplessness; Stress; Symptoms; T cell differentiation; T cell response; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Time; Treatment Efficacy; Veterans; War; Wild Type Mouse; acute stress; base; biological adaptation to stress; classical conditioning; combat; cytokine; effective therapy; efficacy testing; insight; mRNA Expression; mouse model; neurobehavioral; neurochemistry; neurotrophic factor; operation; preclinical study; prevent; protective effect; protective efficacy; psychological stressor; reconstitution; regenerative; repaired; research study; resilience; response; stress related disorder; stressor; therapeutic development; trafficking

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) is one of the most common war-related illness and is highly comorbid with other anxiety disorders. Veterans from the recent Iraq and Afghanistan wars (Operation Enduring Freedom/Operation Iraqi Freedom) have a particularly high incidence of PTSD and other mental disorders such as anxiety and mood disorders. A significant problem for the treatment of PTSD is the lack of an appropriate pharmacological or biological intervention to treat the illness. Indeed, current medications for PTSD are used to treat associated symptoms such as depression or sleep problems and there in no formulation that effectively treat PTSD. Recent studies indicate that T lymphocytes are protective against the development of posttraumatic stress and anxiety as suggested by studies in mice. These studies show that boosting T cell mediated responses confer protection against the development of anxiety and startle responses to stress after acute exposure to predator odor. These studies further indicate that mice deficient of T cell responses are more susceptible to the effects of stress. This is in agreement with our preliminary results suggesting that other mice models of T cell deficiency are more susceptible to the development of anxiety after acute stress exposure and that reconstitution with CD4+ T cells from wild type restore adaptive responses to stress. The objective of the present application is to validate and establish a mice model of T cell function in anxiety and stress-related disorders to study the role of T cells in conferring protection against posttraumatic stress and anxiety. The central hypothesis is that T cells will confer protection to psychogenic stress by trafficking into the brain where they will stimulate the production of neurotrophic factors. It is further hypothesized that polarized T helper type 2 (TH2) cells will mediate these effects while TH1 will favor the development of pathological stress responses. To test, we will employ the RAG2-/- deficient mice which lack functional T and B cells and reconstitution of T cells by adoptive transfer from BALB/c wild type mice in 2 behavioral models of PTSD. In vitro differentiation of T cells will be applied to test the role of TH2 vs TH1 lymphocytes on posttraumatic stress and anxiety. BALB/c wild type, RAG2-/- and RAG2-/- mice reconstituted with differentiated T cells will be evaluated in the exposure to predator odor paradigm or in the extinction of conditioned Pavlovian fear responses. The first paradigm models acute exposure to psychogenic stress and later responses to stress and anxiety and the second paradigm models maladaptive fear responses. These 2 paradigms model key aspects of brain function which are affected in PTSD. Real-time RT-PCR will be used to compare cytokine mRNA expression in the brain to evaluate brain inflammatory responses and the effects of T cell treatment. These responses will be compared with peripheral levels of cytokines determined by ELISA. Immunohistochemistry and confocal microscopy will be employed to analyze the presence of T cells in the brain and the expression of neurotrophic factors. In specific aim #1we will compare behavioral, immunological and neurochemical responses between BALB/c wild type and RAG2-/- mice. In specific aim #2 we will test the effects of reconstituting RAG2-/- mice with differentiated TH2 cells and in specific aim #3 we will test the effects of reconstituting RAG2-/- mice with differentiated TH1 cells in behavioral, immunological and neurochemical responses. The experiments and studies proposed in this application are aimed at establishing a pre-clinical model of neuroimmune function in PTSD and to test the role of differentiated T cells in psychogenic traumatic stress and anxiety. These studies may provide insight into cellular mechanisms of resilience to psychogenic stress that when stimulated may provide regenerative and repair functions in the brain and restore normal stress responses and behavior. This will assist in the development of new and more effective strategies of intervention for the treatment of PTSD and anxiety-related disorders. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorders (PTSD) are highly prevalent in veterans of the Iraq and Afghanistan war zones. Current pharmacological treatments with psychotropic medications display poor efficacy and are generally aimed at treating associated symptoms rather than the illness. The present studies will evaluate if processes mediated by T cells confer protection against the development of posttraumatic stress and anxiety. It is hypothesized that TH2 cells will traffic to the brain after exposure to acute stress where they will stimulate the release of neurotrophic factors conferring protection against deleterious effects of stress. These studies are based upon recent findings suggesting that T cells may prevent the development of anxiety and exaggerated stress responses in a mice model of PTSD. These studies are aimed at establishing an animal model to test the efficacy of treatments with T cells to restore normal stress responses and protect against PTSD and anxiety disorders.

描述（由申请人提供）： 创伤后应激障碍（PTSD）是最常见的战争相关疾病之一，并且与其他焦虑症高度共存。最近参加过伊拉克和阿富汗战争（持久自由行动/伊拉克自由行动）的退伍军人患有创伤后应激障碍（PTSD）和其他精神障碍（例如焦虑和情绪障碍）的发病率特别高。治疗 PTSD 的一个重要问题是缺乏适当的药理学或生物干预措施来治疗该疾病。事实上，目前治疗 PTSD 的药物用于治疗相关症状，如抑郁或睡眠问题，并且没有有效治疗 PTSD 的制剂。 最近的研究表明，正如小鼠研究表明的那样，T 淋巴细胞可以防止创伤后应激和焦虑的发生。这些研究表明，增强 T 细胞介导的反应可以防止在急性暴露于捕食者气味后产生焦虑和对压力的惊吓反应。这些研究进一步表明，缺乏 T 细胞反应的小鼠更容易受到压力的影响。这与我们的初步结果一致，表明其他 T 细胞缺陷小鼠模型在急性应激暴露后更容易出现焦虑，并且用野生型 CD4+ T 细胞重建可恢复对应激的适应性反应。本申请的目的是验证并建立T细胞在焦虑和应激相关疾病中的功能的小鼠模型，以研究T细胞在针对创伤后应激和焦虑提供保护方面的作用。核心假设是，T 细胞将通过运输到大脑中来刺激神经营养因子的产生，从而对心因性应激提供保护。进一步假设极化 2 型辅助 T (TH2) 细胞将介导这些效应，而 TH1 将有利于病理应激反应的发展。为了进行测试，我们将在两种 PTSD 行为模型中使用缺乏功能性 T 和 B 细胞的 RAG2-/- 缺陷型小鼠，并通过从 BALB/c 野生型小鼠过继转移来重建 T 细胞。 T 细胞的体外分化将用于测试 TH2 与 TH1 淋巴细胞对创伤后应激和焦虑的作用。将评估用分化 T 细胞重建的 BALB/c 野生型、RAG2-/- 和 RAG2-/- 小鼠暴露于捕食者气味范式或条件性巴甫洛夫恐惧反应消退的情况。第一个范式模拟了对心因性压力的急性暴露以及随后对压力和焦虑的反应，第二个范式模拟了适应不良的恐惧反应。这两种范式模拟了受 PTSD 影响的大脑功能的关键方面。实时RT-PCR将用于比较大脑中细胞因子mRNA的表达，以评估大脑炎症反应和T细胞治疗的效果。这些反应将与 ELISA 测定的外周细胞因子水平进行比较。将采用免疫组织化学和共聚焦显微镜来分析大脑中 T 细胞的存在以及神经营养因子的表达。在具体目标#1中，我们将比较 BALB/c 野生型和 RAG2-/- 小鼠之间的行为、免疫和神经化学反应。在具体目标#2中，我们将测试用分化的TH2细胞重建RAG2-/-小鼠的效果，在具体目标#3中，我们将测试用分化的TH1细胞重建RAG2-/-小鼠在行为、免疫和神经化学反应中的效果。 本申请提出的实验和研究旨在建立 PTSD 神经免疫功能的临床前模型，并测试分化 T 细胞在心因性创伤应激和焦虑中的作用。这些研究可能有助于深入了解心理应激的细胞机制，当受到刺激时，可能会在大脑中提供再生和修复功能，并恢复正常的应激反应和行为。这将有助于制定新的、更有效的干预策略来治疗创伤后应激障碍和焦虑相关疾病。 公共卫生相关性： 创伤后应激障碍 (PTSD) 在伊拉克和阿富汗战区的退伍军人中非常普遍。目前使用精神药物的药物治疗效果不佳，并且通常旨在治疗相关症状而不是疾病。目前的研究将评估 T 细胞介导的过程是否能提供针对创伤后应激和焦虑发展的保护作用。据推测，TH2 细胞在受到急性压力后会流入大脑，刺激神经营养因子的释放，从而防止压力的有害影响。这些研究基于最近的研究结果，表明 T 细胞可以防止 PTSD 小鼠模型中焦虑和过度应激反应的发展。这些研究旨在建立动物模型来测试 T 细胞治疗恢复正常应激反应并预防 PTSD 和焦虑症的功效。