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：尽管有大量研究描述了神经免疫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仍然是一个研究不足的领域。无胸腺大鼠（缺乏成熟 T 淋巴细胞）和 MHC II 敲除 (KO) 小鼠（CD4+ T 淋巴细胞数量减少）的事实显着减轻了神经损伤后的机械性异常性疼痛，凸显了 T 淋巴细胞在神经性疼痛中的重要作用。该提案将描述神经损伤后中枢神经系统（CNS）浸润性T淋巴细胞的特征，并提供它们在CNS中双向相互作用的机制，从而建立一个模型系统来研究可能的适应性免疫反应相关的治疗靶点（例如CD40） -CD40L 阻断）治疗神经性疼痛。将使用一种完善的神经性疼痛啮齿动物模型，L5 脊髓神经横断（L5Tx），并通过触觉敏感性反应（人类机械超敏反应的代表）来测量小鼠的疼痛行为。我们假设神经损伤激活的 CD4+ T 淋巴细胞浸润到脊髓受影响区域，并通过细胞表面 CD40-CD40L 接合与小胶质细胞（单核细胞来源的中枢神经系统驻留细胞）相互作用，进一步促进小胶质细胞产生促炎细胞因子，这是影响脊髓损伤的重要因素。保持持久的疼痛行为。这项研究将按照以下 3 个具体目标进行：确定 1）L5Tx 后腰脊髓中小胶质细胞 CD40 表达与浸润性 CD4+ T 淋巴细胞 CD40L 表达之间的时间和空间关系，2）小胶质细胞 CD40- 的参与使用 CD4KO 小鼠、涉及 CD40KO 的骨髓嵌合体，在 L5Tx 诱导的机械超敏反应中连接 CD4+ T 淋巴细胞 CD40L小鼠和 CD40 阻断抗体，以及 3) L5Tx 后 CNS CD40-CD40L 相互作用诱导的小胶质细胞促炎细胞因子的产生。公共健康相关性：神经性疼痛被定义为由神经系统原发性病变或功能障碍引发或引起的疼痛，是最具破坏性的慢性疼痛之一，也是与 HIV 感染相关的常见神经并发症，影响着 3-500 万人。每年都有人在美国。然而，它在很大程度上仍然没有得到最佳处理。这项研究将进一步研究适应性免疫在神经性疼痛病理生理学中的作用，并可能为新的非成瘾治疗提供思路。