Mechanisms of Complement-Mediated Damage in SCI

描述（由申请人提供）：先前的研究已经研究了脊髓损伤（SCI）后的细胞炎症反应和炎症细胞因子的调节。据预测，炎症细胞的浸润和相应的细胞因子的产生可通过多种机制导致继发性损伤，研究表明，抑制炎症可能有利于恢复。相反，其他研究提出了一种诱人的可能性，即至少在某些条件下，刺激细胞免疫系统可能提供神经保护作用或增强中枢神经系统损伤的恢复。然而，关键的是，这些炎症事件的主要体液免疫成分，补体级联，尚未被研究。虽然抗体是同源（宿主）防御的关键组成部分，补体是先天和适应性免疫系统的主要效应器。我们的初步数据为以下方面提供了新的证据：1)脊髓损伤后补体免疫反应与神经元、少突胶质细胞和轴突相关；2)改善挫伤大鼠补体耗竭后的功能恢复和组织学结果；3)改善补体C5成分缺乏小鼠的功能恢复。在本研究中，我们研究了补体耗竭在脊髓损伤中的作用机制，脊髓损伤后补体的细胞来源，以及补体介导的损伤在脊髓损伤后功能恢复和组织损伤中的主要途径。我们假设：1)补体耗损引起的功能改善将与抑制中性粒细胞、巨噬细胞/单核细胞、微细胞和t细胞募集、抑制神经元和少突胶质细胞损失以及减少胶质瘢痕形成有关；2)除了损伤后立即血脊髓屏障（BSB）开放的血清来源补体外，局部中枢神经系统细胞合成是脊髓损伤后补体沉积的一个组成部分；3)补体介导的损伤在脊髓损伤后的功能恢复和组织损伤激活中主要依赖于终末通路。这些研究将提供对脊髓损伤后补体活化的具体病理作用的理解，并阐明治疗性脊髓损伤补体抑制的合适潜在靶点，随着新的补体抑制剂被引入CNS损伤的临床试验，这些研究将变得越来越重要。

DESCRIPTION (provided by applicant): Previous studies have investigated the cellular inflammatory response and regulation of inflammatory cytokines following spinal cord injury (SCI). Infiltration of inflammatory cells and corresponding cytokine production has been predicted to contribute to secondary injury via several mechanisms, and studies suggest that inhibition of inflammation can be beneficial to recovery. Conversely, other studies have raised the tantalizing possibility that, at least under some conditions, stimulation of the cellular immune system may provide neuroprotective benefits or enhance recovery from CNS injury. Critically, however, the principal humoral immune component of these inflammatory events, the complement cascade, has not been investigated. While antibodies are a critical component of homologous (host) defense, complement is a principal effector of both the innate and adaptive immune system. Our preliminary data provide novel evidence for: 1) complement immunoreactivity in association with neurons, oligodendrocytes, and axons after SCI, 2) improved functional recovery and histological outcome following complement depletion in contusion-injured rats, and 3) improved functional recovery in mice deficient in the C5 component of complement. In this proposal, we investigate the mechanism of action of complement depletion in SCI, cellular source of complement after SCI, and predominant pathway(s) for complement-mediated impairments in functional recovery and tissue damage after SCI. We hypothesize that: 1) The functional improvements derived from complement depletion will be associated with inhibition of neutrophil, macrophage/monocyte, microgial, and T-cell recruitment, inhibition of neuron and oligodendrocyte cell loss, and reduction in glial scar formation; 2) In addition to serum-derived complement from Blood-Spinal Barrier (BSB) opening immediately after injury, local CNS cell synthesis is a component of complement deposition after SCI; and 3) Complement-mediated impairments in functional recovery and tissue damage activation after SCI are predominantly dependent upon the terminal pathway. These studies will provide an understanding of the specific pathological role of complement activation after SCI, and clarify appropriate potential targets for therapeutic complement inhibition in SCI, which will be increasingly important as new complement inhibitors are brought to clinical trials for CNS injury.