Nerve Allotransplantation for Traumatic Nerve Injury

这项建议的长期目标是将供者特异性免疫无反应、神经移植物注射与培养的自体雪旺细胞以及免疫抑制剂FK506相结合，以促进同种异体神经移植物的再生。对主要外周神经的损伤可导致严重的永久性功能缺陷。同种异体神经移植材料的使用可以避免自体神经移植的并发症，如瘢痕、麻木或痛性神经瘤的形成，为修复大型、多发和复杂的神经损伤提供了无限的神经移植材料来源。全身性免疫抑制剂FK506显著促进神经再生。注射培养的自体雪旺细胞的同种异体移植可以在啮齿动物模型中实现轴突再生。单独应用抗CD40配体单抗可促进小鼠同种异体神经移植。在同种异体神经移植前，用UVB照射的供体抗原进行预处理，可诱导免疫无反应，并促进啮齿动物和猪模型的神经再生。猪和非人类灵长类动物模型已经被开发出来，用于研究同种异体神经移植在较长的神经间隙中的再生，这更接近于重建广泛神经损伤的临床挑战。这项建议的目的是：1.)目的：探讨神经增强型免疫抑制剂FK506联合抗CD40配体单抗诱导的供体特异性免疫无反应对小鼠移植神经再生的影响。2.)目的：探讨自体雪旺细胞移植对猪和非人灵长类动物同种异体长神经移植免疫抑制需求和轴突再生的影响。评估技术包括混合淋巴细胞培养、细胞毒性T淋巴细胞分析和有限稀释分析，以及神经再生的组织学、形态学、电生理学和功能评估。这项建议的主要目的是改善人类同种异体神经移植后的结果。

The long term goal of this proposal is to combine donor- specific immune unresponsiveness, nerve graft injection with cultured autologous Schwann cells, and the immunosuppressive agent FK506 to promote regeneration across nerve allografts. Injury to major peripheral nerves can result in significant and permanent functional deficits. The use of allogeneic nerve graft material would avoid the morbidity associated with harvesting nerve autografts, such as scars, numbness or painful neuroma formation, and offer a limitless source of nerve graft material to reconstruct large, multiple and complex nerve injuries. The systemic immunosuppressive agent FK506 significantly enhances nerve regeneration. Allograft injection with cultured autologous Schwann cells permits axonal regeneration in a rodent model. Administration of anti-CD40 ligand monoclonal antibody alone facilitates nerve allotransplantation in a murine model. Pre- treatment with UVB-irradiated donor antigen prior to nerve allotransplantation induces immune unresponsiveness and facilitates nerve regeneration in both rodent and swine models. Reliable swine and nonhuman primate models have been developed to study nerve allograft regeneration across a long nerve gap that more closely resembles the clinical challenge of reconstruction of extensive nerve injuries. The aims of this proposal are: 1.) To investigate the effects of combining the neuroenhancing immunosuppressive drug FK506 with anti-CD40 ligand monoclonal antibody induced donor-specific immune unresponsiveness on regeneration across short nerve allografts in a murine model. 2.) To investigate the effects of graft injection with cultured autologous Schwann cells on immunosuppressive requirements and axonal regeneration in long nerve allografts in swine and nonhuman primate models. Assessment techniques include mixed lymphocyte culture, cytotoxic T-lymphocyte assays and limiting dilutional analysis, in conjunction with histological, morphological, electrophysiological, and functional assessments of nerve regeneration. The broad objective of this proposal is to improve the results following human nerve allotransplantation.