Nerve Allotransplantation for Traumatic Nerve Injury

该提案的长期目标是将联合收割机供体特异性免疫无反应性、神经移植物注射与培养的自体施万细胞和免疫抑制剂FK 506结合以促进神经同种异体移植物的再生。主要周围神经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与收获神经自体移植物相关的发病率，例如疤痕、麻木或疼痛性神经瘤形成，并提供无限的神经移植材料来源以重建大的、多个和复杂的神经损伤。全身性免疫抑制剂FK 506显著增强神经再生。 同种异体移植物注射培养的自体雪旺细胞允许啮齿动物模型中的轴突再生。抗CD40配体单克隆抗体单独给药促进小鼠模型中的同种异体神经移植。 在啮齿动物和猪模型中，在神经同种异体移植之前用UVB照射的供体抗原预处理诱导免疫无反应性并促进神经再生。已经开发了可靠的猪和非人灵长类动物模型来研究长神经间隙的神经同种异体移植物再生，这更接近于重建广泛神经损伤的临床挑战。本提案的目的是：（1）研究神经增强免疫抑制药物FK506联合抗CD40配体单克隆抗体诱导的供体特异性免疫无反应性对小鼠同种异体短神经移植物再生的影响。 2.）在猪和非人灵长类动物模型中，研究移植物注射培养的自体雪旺细胞对长神经同种异体移植物中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。 这项建议的广泛目标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.