Role of Infiltrating CD4+ T Lympoocytes in Neuropathic Pain

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。

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.