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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

基本信息

批准号：
7792213
负责人：
Ling Cao
金额：
$ 12.78万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7792213
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 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 adaptive immunity 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

项目摘要

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）：尽管有许多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。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）在神经损伤后出现明显减少的机械性异常痛，这一事实突出了T淋巴细胞在神经性疼痛中的重要作用。本研究将描述神经损伤后中枢神经系统（CNS）浸润T淋巴细胞的特征，并提供它们在中枢神经系统中双向相互作用的机制，从而为研究神经性疼痛中可能的适应性免疫反应相关治疗靶点（如CD40-CD40L阻断）建立模型系统。一个完善的啮齿动物神经性疼痛模型，L5脊神经横断（L5Tx），将被使用和疼痛行为的小鼠将通过触觉敏感反应来测量，这是人类机械超敏反应的一种表现。我们假设神经损伤激活CD4+ T淋巴细胞浸润到脊髓受损伤区域，并通过细胞表面CD40-CD40L参与与小胶质细胞（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，这是维持持久疼痛行为的重要因素。本研究将进行以下3个具体目的：利用CD4KO小鼠、CD40KO小鼠骨髓嵌合体和CD40阻断抗体，确定1)l5tx后腰椎小胶质细胞CD40表达与浸润性CD4+ T淋巴细胞CD40L表达的时空关系；2)小胶质细胞CD40-CD4+ T淋巴细胞CD40L结扎在l5tx诱导的机械超敏反应中的作用。3) l5tx后CNS CD40-CD40L相互作用诱导的小胶质促炎细胞因子的产生。公共卫生相关性：神经性疼痛，定义为由神经系统原发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系统并发症，每年在美国影响300 - 500万人。然而，它在很大程度上仍然是次优的。本研究将进一步探讨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性治疗提供思路。