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.
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