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.
|Malon, Jennifer T; Cao, Ling (2016) Preparation of Primary Mixed Glial Cultures from Adult Mouse Spinal Cord Tissue. J Vis Exp :|
|Draleau, Ks; Maddula, S; Slaiby, A et al. (2014) Phenotypic Identification of Spinal Cord-Infiltrating CD4(+) T Lymphocytes in a Murine Model of Neuropathic Pain. J Pain Relief Suppl 3:003|
|Cao, Ling; Beaulac, Holly; Eurich, Adriana (2012) Differential lumbar spinal cord responses among wild type, CD4 knockout, and CD40 knockout mice in spinal nerve L5 transection-induced neuropathic pain. Mol Pain 8:88|
|Malon, Jennifer T; Maddula, Swathi; Bell, Harmony et al. (2011) Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain. Neuron Glia Biol 7:117-28|
|Cao, Ling; Palmer, Christopher D; Malon, Jennifer T et al. (2009) Critical role of microglial CD40 in the maintenance of mechanical hypersensitivity in a murine model of neuropathic pain. Eur J Immunol 39:3562-9|