Nerve Allotransplantation for Traumatic Nerve Injury

本研究的长期目标是结合供体特异性免疫无反应性、神经移植物注射培养的自体雪旺细胞和免疫抑制剂FK506来促进同种异体神经移植物的再生。主要周围神经的损伤可导致严重和永久性的功能缺陷。同种异体神经移植材料的使用将避免自体神经移植带来的并发症，如疤痕、麻木或疼痛的神经瘤形成，并提供无限的神经移植材料来源来重建大的、多的和复杂的神经损伤。全身免疫抑制剂FK506显著促进神经再生。同种异体移植注射培养的自身雪旺细胞允许轴突再生的啮齿动物模型。单独给药抗cd40配体单克隆抗体促进小鼠模型神经异体移植。在同种异体神经移植前，用uvb照射供体抗原进行预处理，可诱导免疫无反应性，促进啮齿动物和猪模型的神经再生。可靠的猪和非人灵长类动物模型已经被开发出来，用于研究跨越长神经间隙的同种异体神经移植再生，这更接近于广泛神经损伤重建的临床挑战。本建议的目的是：1)；目的探讨神经增强免疫抑制药物FK506联合抗cd40配体单克隆抗体诱导供体特异性免疫无反应性对小鼠短神经异体移植再生的影响。2)。目的探讨体外培养的自体雪旺细胞对猪和非人灵长类动物长神经移植物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淋巴细胞测定和限制性稀释分析，以及神经再生的组织学、形态学、电生理和功能评估。该建议的主要目的是改善人类神经同种异体移植后的结果。

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.