Mechanisms of Complement-Mediated Damage in SCI

描述（由申请人提供）：以前的研究已经调查了脊髓损伤（SCI）后的细胞炎症反应和炎症细胞因子的调节。已经预测炎症细胞的浸润和相应的细胞因子产生通过几种机制促成继发性损伤，并且研究表明抑制炎症可以有益于恢复。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益处或促进CNS损伤的恢复。然而，至关重要的是，这些炎症事件的主要体液免疫成分，补体级联反应，尚未进行研究。虽然抗体是同源（宿主）防御的关键组分，但补体是先天性和适应性免疫系统的主要效应子。我们的初步数据提供了新的证据：1）补体免疫反应性与神经元，少突胶质细胞和轴突脊髓损伤后，2）改善功能恢复和组织学结果后，补体消耗挫伤大鼠，和3）改善功能恢复在小鼠补体C5成分缺乏。在这个提议中，我们研究了SCI中补体耗竭的作用机制，SCI后补体的细胞来源，以及SCI后功能恢复和组织损伤中补体介导的损伤的主要途径。我们假设：1）源自补体耗竭的功能改善将与抑制中性粒细胞、巨噬细胞/单核细胞、小胶质细胞和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相关; 2）除了在损伤后立即开放血脊髓屏障（BSB）的血清来源的补体之外，局部CNS细胞合成是SCI后补体沉积的组分;和3）SCI后功能恢复和组织损伤激活中的补体介导的损伤主要依赖于终末途径。这些研究将提供对SCI后补体激活的特定病理学作用的理解，并阐明SCI中治疗性补体抑制的适当潜在靶点，随着新的补体抑制剂用于CNS损伤的临床试验，这将变得越来越重要。

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.