NERVE ALLOTRANSPLANTATION FOR TRAUMATIC NERVE INJURY

临床可应用的诱导策略的建立 允许同种异体神经移植的供者特异性耐受性是 这项提议的长期目标。主要外周损伤 神经可能导致严重的、永久性的功能缺陷。 使用同种异体神经移植材料可避免并发症的发生。 与获取自体神经移植物有关，如疤痕，麻木， 或痛苦的神经瘤形成，并提供无限的神经来源 移植材料重建大、多、复杂神经 受伤。保存同种异体神经移植的参数 已建立的和冷保存的移植物被认为减少了系统性 环孢素A(CsA)要求。单抗(MAbs) 黏附分子ICAM-1和LFA-1抑制同种异体神经移植 反应，但不能容忍动物。相比之下，特定于捐赠者的 UV-B照射的脾细胞抗原预处理诱导 大鼠同种异体移植模型的耐受性。抗CD4mAbs灭活 功能正常的T细胞，从而导致宿主无反应。一个 已建立了可靠的绵羊模型来研究同种异体神经移植 在长的神经缝隙中再生，更接近于 广泛神经损伤重建的临床挑战。七 同种异体神经移植冷保存天数减少 同种异体移植物的抗原性，并允许神经再生。因此， 与实体器官移植不同，保存同种异体移植使 受体经UV-B辐射供体抗原预处理(7天前) 异体移植在临床上是可行的。这项提议的目的是 是：1)建立一种免疫抑制策略，使用预转录- 供体抗原联合抗CD4mAb局部注射 同种异体短神经移植诱导供体特异性耐受的治疗 2)研究冷神经保存环孢素A的优点。 治疗和给予供体抗原以授予免疫力- NCE建立绵羊同种异体神经移植模型。评估技术将 包括混合淋巴细胞培养、细胞毒性T淋巴细胞检测和 极限稀释分析，结合组织学、形态分析。 神经的逻辑、电生理和功能评估 再生。这项建议的主要目标是改善 同种异体神经移植后的结果，从而允许建立 神经库和临床同种异体神经移植的便利- 提顿。

The establishment of clinically applicable strategies for inducing donor-specific tolerance to allow nerve allograft transplantation is the long term objective of this proposal. 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. Parameters for nerve allograft preservation have been established and cold graft preservation is seen to decrease systemic Cyclosporin A (CsA) requirements. Monoclonal antibodIes (mAbs) against adhesion molecules, ICAM-1 and LFA-1, suppress the nerve allograft response but do not tolerize the animal. By contrast, donor-specific antigen pretreatment with UV-B irradiated spleen cells induces tolerance in the rat allograft model. Anti-CD4 mAbs inactivate functional T cells and thus, result in host unresponsiveness. A reliable sheep model has 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. Seven days of cold preservation of the nerve allograft decreases the antigenicity of the allograft and allows nerve regeneration. Thus, unlike solid organ transplantation, preservation of the allograft makes recipient pretreatment with UV-B irradiated donor antigen(7 days) prior to allotransplantation clinically feasible. The aims of this proposal are: 1) to establish an immunosuppressive strategy that uses pretransp- lant administration of donor antigen in combination with anti-CD4 mAb therapy to induce donor-specific tolerance in a short nerve allograft rat model; and 2) to study the merits of cold nerve preservation CsA therapy and the administration of donor antigen to confer immunotolera- nce to along nerve allograft sheep model. Assessment techniques will include mixed lymphocyte culture, cytotoxic T lymphocyte assays and limiting dilutional analysis, in conjunction is histological, morpho- logical, electrophysiological and functional assessment of nerve regeneration. The broad objective of this proposal is to improve the results following nerve allografting and thus allow the establishment of a nerve bank and the facilitation of clinical nerve allotransplanta- tion.