Role of Infiltrating CD4+ T Lympoocytes in Neuropathic Pain

描述(申请人提供)：描述：尽管有许多研究描绘了神经免疫反应在神经病理性疼痛中的作用，但获得性免疫在神经病理性疼痛中的作用仍是一个研究不足的领域。无菌大鼠(缺乏成熟T淋巴细胞)和MHC II基因敲除(KO)小鼠(CD4+T淋巴细胞数量减少)在神经损伤后发生的机械性痛觉异常显著减少，这一事实突显了T淋巴细胞在神经病理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)T淋巴细胞的特点，并为其在中枢神经系统内的双向相互作用提供机制，从而建立一个研究神经病理性疼痛中可能的获得性免疫反应相关治疗靶点(如CD40-CD40L阻断)的模型系统。将使用一种成熟的神经病理性疼痛的啮齿动物模型，L5脊髓神经横断术(L5Tx)，并将通过触觉敏感性反应来衡量小鼠的疼痛行为，触觉敏感性反应是人类机械过敏的代表。我们假设，神经损伤激活的CD4+T淋巴细胞渗透到脊髓的受累区域，并通过细胞表面CD40-CD40L的参与与小胶质细胞(单核细胞起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，这是维持长期疼痛行为的重要因素。本研究将进行以下三个方面的研究：1)L5Tx后脊髓小胶质细胞CD40表达与CD40L浸润性CD4+T淋巴细胞表达之间的时空关系；2)小胶质细胞CD40-CD4+T淋巴细胞CD40L结扎在L5Tx诱导的机械性超敏反应中的作用。公共卫生相关性：神经性疼痛是指由神经系统的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，也是与艾滋病毒感染相关的常见神经系统并发症，在美国每年影响300-500万人。然而，它在很大程度上仍被视为次优。这项研究将进一步探讨获得性免疫在神经病理性疼痛的病理生理学中的作用，并可能为非成瘾治疗提供新的思路。

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.