Role of Infiltrating CD4+ T Lympoocytes in Neuropathic Pain

浸润性 CD4 T 淋巴细胞在神经性疼痛中的作用

• 批准号: 7587314
• 负责人: Ling Cao
• 金额: $ 12.56万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587314
• 关键词: Affect; Area; Biological Models; Blocking Antibodies; Bone Marrow; CD4 Positive T Lymphocytes; Cell surface; Cells; Chimera organism; Complication; Confocal Microscopy; Flow Cytometry; Functional disorder; HIV Infections; Human; Hypersensitivity; Immune response; Immunity; Interleukin-1; Interleukin-6; Interleukins; Knock-out; Knockout Mice; Leukocytes; Ligation; Lumbar spinal cord structure; Mature T-Lymphocyte; Measures; Mechanics; Microglia; Mus; Necrosis; Nervous system structure; Neuraxis; Neurologic; Nude Rats; Pain; Peripheral; Primary Lesion; Production; Rodent Model; Role; Signal Transduction; Spinal Cord; Spinal nerve structure; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Tactile; Testing; Time; Wild Type Mouse; chronic pain; cytokine; immunoreactivity; irradiation; mechanical allodynia; monocyte; nerve injury; pain behavior; painful neuropathy; public health relevance; response; sham surgery; spatial relationship; therapeutic target; tumor

DESCRIPTION (provided by applicant): Description: Despite there being numerous studies delineating the role of neuroimmue responses in neuropathic pain, the role of adaptive immunity in neuropathic pain is yet an under-studied area. The fact that athymic rats (that lack mature T lymphocytes) and MHC II knockout (KO) mice (who have decreased numbers of CD4+ T lymphocytes) developed significantly reduced mechanical allodynia following nerve injury highlight the significant role of T lymphocytes in neuropathic pain. This proposal will characterize the central nervous system (CNS) infiltrating T lymphocytes after nerve injury and provide a mechanism for their bi-directional interactions in the CNS, thus establishing a model system for investigating possible adaptive immune response-related therapeutic targets (such as CD40-CD40L blockade) in neuropathic pain. A well-established rodent model of neuropathic pain, L5 spinal nerve transection (L5Tx), will be used and pain behavior in mice will be measured by the tactile sensitivity response, a representation of mechanical hypersensitivity in humans. We hypothesize that nerve injury activated CD4+ T lymphocytes infiltrate into the affected region of the spinal cord and interact with microglia (the CNS resident cells of monocyte origin) via cell surface CD40-CD40L engagement, further promoting microglial production of proinflammatory cytokines, factors important in maintaining long-lasting pain behavior. This study will be carried out following 3 specific aims: Determine 1) the temporal and spatial relationships between microglial expression of CD40 and infiltrating CD4+ T lymphocyte expression of CD40L in the lumbar spinal cord post-L5Tx, 2) the involvement of the microglial CD40-CD4+ T lymphocyte CD40L ligation in L5Tx-induced mechanical hypersensitivity by using CD4KO mice, bone marrow chimeras involving CD40KO mice, and a CD40 blocking antibody, and 3) the microglial proinflammatory cytokine production induced by the CNS CD40-CD40L interaction post-L5Tx. Public Health Relevance: Neuropathic pain, defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system, is one of the most devastating kinds of chronic pain, and a common neurological complication associated with HIV infection, affecting 3-5 million people every year in the US. However, it is still largely treated sub-optimally. This study will further investigate the role of adaptive immunity in the pathophysiology of neuropathic pain and may yield ideas for new non-addictive treatments.

描述（由申请人提供）：描述：尽管有许多研究描述了神经疗法反应在神经性疼痛中的作用，但适应性免疫在神经性疼痛中的作用却是一个研究不足的领域。无胸腺大鼠（缺乏成熟的T淋巴细胞）和MHC II敲除（KO）小鼠（减少CD4+ T淋巴细胞数量）在神经损伤后发生机械性异常性疾病显着降低了神经性疼痛中T淋巴细胞的重要作用。该提案将表征神经损伤后中枢神经系统（CNS）浸润T淋巴细胞，并为其在中枢神经系统中提供双向相互作用的机制，从而建立了一种模型系统，用于研究可能与适应性免疫反应相关的治疗靶点（例如CD40-CD40L loke）（例如CD40-CD40L封锁）。将使用一个完善的神经性疼痛的啮齿动物模型，L5脊柱神经横断（L5TX），将使用小鼠的疼痛行为，通过触觉敏感性反应来衡量，这是人类机械性超敏反应的表示。我们假设神经损伤通过细胞表面CD40-CD40L参与度激活CD4+ T淋巴细胞进入脊髓的影响区域，并与小胶质细胞（单核细胞起源的CNS驻留细胞）相互作用，进一步促进促膜细胞动力学的小胶质细胞产生，以维持痛苦的痛苦。这项研究将按照3个具体目的进行：确定1）CD40的小胶质表达与浸润CD4+ T淋巴细胞表达CD40L的时间和空间关系在LBAR脊髓后L5TX中，2）2）2）使用小胶质细胞CD40-CD4+ T lymphocyte lymphocyte lymphocialdient cd40-cd4+ t lymphocyte in。 CD4KO小鼠，涉及CD40KO小鼠的骨髓嵌合体和CD40阻断抗体以及3）CNS CD40-CD40L相互作用在L5TX后诱导的小胶质细胞促炎细胞因子产生。公共卫生相关性：神经性疼痛被定义为神经系统中原发性病变或功能障碍引起或引起的疼痛，是最毁灭性的慢性疼痛之一，并且是与HIV感染相关的常见神经系统并发症，每年影响3-500万人。但是，它仍然在很大程度上进行了优化的治疗。这项研究将进一步研究适应性免疫在神经性疼痛的病理生理学中的作用，并可能对新的非依恋治疗产生思想。