T-cell Functions in the Injured Spinal Cord

描述(申请人提供)：脊髓损伤(SCI)触发神经炎症反应，可加剧组织损伤，促进受损神经元和神经胶质细胞的修复。开发免疫介导的修复机制和拮抗降解性免疫级联反应具有治疗价值。不幸的是，这些机制和细胞/体液级联仍然是个谜。到目前为止，对脊髓损伤后神经炎症的研究主要集中在中性粒细胞、小胶质细胞和/或巨噬细胞。然而，T淋巴细胞也渗透到损伤的脊髓中；然而，它们在继发性变性和修复过程中的作用尚不清楚。鉴于T细胞直接影响血脑屏障的完整性、轴突传导、细胞外基质组成、巨噬细胞/小胶质细胞的功能和神经元/神经胶质细胞的存活，活化的T细胞无疑影响脊髓损伤后的恢复。我们已经证明，脊髓损伤启动了外周T细胞的激活(即增殖和细胞因子的产生)，激活的T细胞渗透到损伤部位。这些细胞如何以及在多大程度上影响脊髓损伤的恢复尚不清楚。Aim 1的研究将评估T细胞对脊髓损伤病理和功能恢复的正常进展的影响。对所有T细胞的系统操作将使用裸鼠和抗体介导的T细胞去除来完成。在目标2中，我们将确定是否可以通过抑制中枢神经系统髓鞘反应性T细胞来改善脊髓损伤的恢复--我们之前已经证明，这种细胞会加剧脊髓损伤后的病理并损害功能恢复。选择性去除髓鞘反应性T细胞将使用临床上可行的口服耐受范例来完成。更新的初步数据也促使我们考虑是否可以利用其他(非髓鞘反应)T细胞用于治疗目的。因此，目标3的研究将确定热休克蛋白反应性T细胞是否可以通过抑制急性神经炎来传递神经保护和促进脊髓损伤的恢复。Aim 4的研究将探索脊髓损伤后T细胞介导的损伤的一个可疑机制，即激活招募的巨噬细胞。这将通过具有增强的髓鞘反应性T细胞功能的巨噬细胞耗竭动物来实现。在这项建议中要检验的主要假设是，T细胞在损伤的脊髓内发挥病理和神经保护作用。这种功能的多样性取决于招募的T细胞的表型和抗原特异性，以及损伤部位的细胞和生化环境。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) triggers a neuroinflammatory reaction that can exacerbate tissue damage and promote repair of injured neurons and glia. Exploitation of immune-mediated repair mechanisms and antagonism of degradative immunological cascades has therapeutic value. Unfortunately, these mechanisms and cellular/humoral cascades remain enigmatic. To date, studies of neuroinflammation after SCI have focused largely on neutrophils, microglia and/or macrophages. However, T-lymphocytes also infiltrate the traumatized spinal cord; yet, their roles in processes of secondary degeneration and repair are poorly defined. Given that T-cells directly influence blood-brain barrier integrity, axonal conduction, extracellular matrix composition, macrophage/microglial function and neuronal/glial survival, activated T-cells undoubtedly affect recovery from SCI. We have demonstrated that SCI primes the activation (i.e., proliferation and cytokine production) of peripheral T-cells and that activated T-cells infiltrate the injury site. How and to what extent these cells influence recovery from SCI is not known. Studies in Aim 1 will evaluate T-cell influences on the normal progression of SCI pathology and functional recovery. A systematic manipulation of all T-cells will be accomplished using nude rats and antibody-mediated depletion of T-cells. In Aim 2, we will determine whether recovery from SCI can be improved by inhibiting CNS myelin-reactive T-cells -- cells that we have previously shown exacerbate pathology and impair functional recovery after SCI. Selective depletion of myelin-reactive T-cells will be accomplished using a clinically feasible oral tolerance paradigm. Newer preliminary data has prompted us to also consider whether other (non-myelin reactive) T-cells can be exploited for therapeutic purposes. Accordingly, studies in Aim 3 will determine whether heat shock protein-reactive T-cells can convey neuroprotection and improve recovery from SCI by suppressing acute neuroinflammation. Studies in Aim 4 will explore a suspected mechanism of T-cell mediated injury after SCI, i.e., activation of recruited macrophages. This will be accomplished by macrophage depleting animals with enhanced myelin-reactive T-cell function. The primary hypothesis to be tested in this proposal is that T-cells exert pathological and neuroprotective effects within the injured spinal cord. This functional diversity depends on the phenotype and antigen-specificity of recruited T-cells as well as the cellular and biochemical milieu at the injury site.