T-cell Functions in the Injured Spinal Cord

描述（由申请人提供）：脊髓损伤（SCI）引发神经炎症反应，可加剧组织损伤并促进受损神经元和神经胶质的修复。开发免疫介导的修复机制和拮抗降解免疫级联反应具有治疗价值。不幸的是，这些机制和细胞/体液级联仍然是谜。迄今为止，SCI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淋巴细胞也浸润创伤的脊髓;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/小胶质细胞功能和神经元/胶质细胞存活，活化的T细胞无疑会影响SCI的恢复。我们已经证明了SCI启动激活（即，增殖和细胞因子产生）和活化的T细胞浸润损伤部位。这些细胞如何以及在多大程度上影响SCI的恢复尚不清楚。目标1中的研究将评估T细胞对SCI病理和功能恢复正常进展的影响。将使用裸大鼠和抗体介导的T细胞耗竭完成所有T细胞的系统操作。在目标2中，我们将确定是否可以通过抑制CNS髓鞘反应性T细胞来改善SCI的恢复-我们以前已经证明SCI后的病理恶化和功能恢复受损的细胞。髓鞘反应性T细胞的选择性消耗将使用临床上可行的口服耐受范例来完成。较新的初步数据促使我们考虑是否可以利用其他（非髓鞘反应性）T细胞用于治疗目的。因此，目标3中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症来传递神经保护并改善SCI的恢复。目的4中的研究将探索SCI后T细胞介导的损伤的可疑机制，即，激活募集的巨噬细胞。这将通过具有增强的髓磷脂反应性T细胞功能的巨噬细胞消耗动物来实现。在这项提议中要检验的主要假设是T细胞在受损的脊髓内发挥病理和神经保护作用。这种功能多样性取决于募集的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.