Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function
Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function
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DOI：
10.1523/jneurosci.5343-03.2004
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发表时间：
2004-04-21
影响因子：
5.3
通讯作者：
Weaver, LC
中科院分区：
文献类型：
--
作者：
Gris, D;Marsh, DR;Weaver, LC
脊髓损伤（SCI）的早期炎症反应会导致严重的继发性损伤。非选择性抑制炎症的策略并没有改善SCI后的结果，这可能是因为SCI后炎症既有不利的影响，也有有益的影响。我们已经表明，选择性的，有时限的行动的单克隆抗体（mAb）的CD 11 d/CD 18整合素的CD 11 d亚基，在第一个48小时内在大鼠脊髓损伤后静脉内交付，显着减少中性粒细胞的浸润，并延迟血单核细胞-巨噬细胞进入受损的脊髓。我们假设，这种有针对性的策略将导致神经保护和改善神经功能的结果。在本研究中，通过评估在第十二胸段处的临床相关夹式压缩SCI后2周至3个月的躯干和后爪上的机械性异常性疼痛，检测大鼠慢性疼痛的发展。抗CD 11 d mAb治疗将这种疼痛减轻了一半。运动表现也有所改善，因为大鼠能够将后爪放在足底并用于重量支撑，而不仅仅是扫地运动。在第四胸段脊髓损伤后，自主神经反射障碍的显著减少显示了心血管结局的改善。运动性能也得到了改善。这些功能变化与病变附近髓鞘和神经丝的显著更大量和增加的组织相关。SCI后早期炎症特异性减少后神经恢复的改善表明，这种选择性策略增加了损伤部位的组织并提高了其功能能力。这种早期的神经保护治疗将是建立后来基于细胞的治疗的理想基础。
The early inflammatory response to spinal cord injury (SCI) causes significant secondary damage. Strategies that nonselectively suppress inflammation have not improved outcomes after SCI, perhaps because inflammation has both adverse and beneficial effects after SCI. We have shown that the selective, time-limited action of a monoclonal antibody (mAb) to the CD11d subunit of the CD11d/CD18 integrin, delivered intravenously during the first 48 hr after SCI in rats, markedly decreases the infiltration of neutrophils and delays the entry of hematogenous monocyte-macrophages into the injured cord. We hypothesized that this targeted strategy would lead to neuroprotection and improved neurological outcomes. In this study the development of chronic pain was detected in rats by assessing mechanical allodynia on the trunk and hindpaws 2 weeks to 3 months after a clinically relevant clip-compression SCI at the twelfth thoracic segment. The anti-CD11d mAb treatment reduced this pain by half. Motor performance also improved as rats were able to plantar-place their hindpaws and use them for weight support instead of sweeping movements only. Improved cardiovascular outcome was shown after SCI at the fourth thoracic segment by significant decreases in autonomic dysreflexia. Locomotor performance was also improved. These functional changes correlated with significantly greater amounts and increased organization of myelin and neurofilament near the lesion. The improved neurological recovery after the specific reduction of early inflammation after SCI demonstrates that this selective strategy increases tissue at the injury site and improves its functional capacity. This early neuroprotective treatment would be an ideal foundation for building later cell-based therapies.