NERVE ALLOTRANSPLANTATION FOR TRAUMATIC NERVE INJURY

描述：主要周围神经损伤可导致严重的 长期功能性缺陷。 这些损伤的处理 对于重建外科医生来说仍然是一个重要的问题， 可用作自体移植物的消耗性皮神经的数量 是有限的。 同种异体神经移植材料的使用将 避免并发症（瘢痕、麻木或神经瘤形成） 与获取神经自体移植物相关， 神经移植材料的来源，以重建大，多， 复杂的神经损伤确立临床适用 同种异体神经移植的策略是一个长期的目标 这将为外科手术提供显著改善的选择， 创伤性周围神经损伤的重建。 这个实验室以前的工作已经证明了成功的神经 环孢素A（CsA）对同种异体移植物再生的影响 免疫抑制以及神经移植的可行性 保存。冷藏（4 ℃）一周以上 显著减少淋巴细胞迁移到同种异体移植物中， 低于相应的自体移植水平。 本研究的具体目标是 确定减少同种异体移植物的最短保存时间， 免疫原性，并研究联合移植物的优点 短期CsA治疗的保存。这些特定的成就 目的将对临床同种异体神经移植产生直接影响。 最近的研究表明，单克隆抗体的潜在疗效 针对ICAM-1和LFA-1的抗体（MAbs）抑制神经 同种异体移植反应 具体目标将涉及这些方面的潜力， 单克隆抗体联合保存和CsA免疫抑制， 显著增强同种异体移植物再生。 的机制 将探索单克隆抗体诱导耐受性。 已经建立了几种动物模型来完成这些特定的 目标。 建立了绵羊淋巴细胞运输模型， 评估淋巴细胞迁移到同种异体神经移植物中。 啮齿动物模型 的神经同种异体移植物排斥反应将被用来研究的疗效， 短程CsA治疗联合最佳神经保留 参数;在有限数量的灵长类动物中，这些结果将 为了便于应用于人类临床， 审判 啮齿动物模型也将用于研究 单克隆抗体诱导成人外周耐受。 评估技术将 包括T-淋巴细胞细胞毒性测定， 组织学、形态学、电生理学和功能 评估神经再生。建立神经银行， 促进临床神经移植是广泛的目标， 这个提议。

DESCRIPTION: Injury to major peripheral nerves can result in significant and long term functional deficits. The management of these injuries continues to be a significant problem for the reconstructive surgeon as the number of expendable cutaneous nerves that can be used as autografts is limited. The use of nerve graft material of allogenic origin would avoid the concomitant morbidity (scar, numbness or neuroma formation) associated with harvesting nerve autografts and offers a limitless source of nerve graft material to reconstruct large, multiple, and complex nerve injuries. Establishment of clinically applicable strategies for nerve allograft transplantation is a long term objective which would offer significant improved options for surgical reconstruction of traumatic peripheral nerve injuries. Previous work from this laboratory has demonstrated successful nerve allograft regeneration under the influence of Cyclosporin A (CsA) immunosuppression as well as the feasibility of nerve allograft preservation. Cold preservation (4 degrees C) for greater than one week reduced lymphocyte migration into the allograft significantly to levels below corresponding autograft levels. Specific aims of this study are to define the minimum preservation time that would decrease allograft immunogenicity and investigate the merits of a combination of graft preservation with short course CsA therapy.Achievement of these specific aims would have immediate impact on clinical nerve allotransplantation. Recent studies have demonstrated the potential efficacy of monoclonal antibodies (MAbs) against ICAM-1 and LFA-1 to suppress the nerve allograft response. Specific aims will address the potential of these Mabs in combination with preservation and CsA immunosuppression to significantly enhance allograft regeneration. The mechanism by which MAbs induce tolerance will be explored. Several animal models have been established to accomplish these specific aims. An ovine model of lymphocyte trafficking has been established to assess lymphocyte migration into the nerve allograft. A rodent model of nerve allograft rejection will be used to study the efficacy of short-course CsA therapy in combination with optimal nerve preservation parameters; in a limited number of primates these results will be confirmed in order to facilitate application toward human clinical trials. The rodent model will also be used to examine the mechanism of MAb induced adult peripheral tolerance. Assessment techniques will include T-lymphocyte cytotoxicity assays in combination with histological, morphological, electrophysiological, and functional assessment of nerve regeneration. Establishment of a nerve bank and the facilitation of clinic nerve transplantation is the broad objective of this proposal.