Grants We Funded

Abstract
Peripheral nerve injuries are frequently seen by plastic surgeons. While it is known that the best result is obtained when those nerve gaps are repaired with auto grafts, auto grafts sometimes may not provide adequate amounts of nerve for reconstruction of long or complex defects (Rodriguez et al. 2000). Tissue-engineered grafts, such as acellularized peripheral nerve grafts, provide a possible solution for reconstruction of gaps less than 2 cm in length (Haase et al. 2003). Unfortunately, no tissue-engineered constructs are efficacious for long (>6 cm) nerve gaps. Peripheral nerve allografts are a potential alternative for reconstruction of long gaps but are limited in their clinical utility due to the need for nonspecific, global immunosuppression. Specifically, the allograft Schwann cells (SCs) behave as antigen-presenting cells leading to cell death and rejection without immunosuppression (Trumble and Shon 2000). Significant attention has been directed towards targeting co-stimulatory pathways as inductive therapy for reducing alloimmune responses and preventing allograft rejection. The CD40-CD40L pathway has received the most academic scrutiny and seems to play a prominent role in T-cell-mediated rejection (Harlan 1999). Blockade of this pathway has been found to produce a permissive state in murine peripheral nerve allografts (Brenner et al. 2004). Strategies to induce tolerance or long-term immunologic hyporesponsiveness following nerve allografting require a better understanding of which SCs populate a nerve allograft in the setting of costimulatory pathway blockade with MRl after nerve-gap reconstruction: donor or recipient SCs. Our hypothesis is that donor nerve SCs do not survive allotransplantation and are rejected if they are not given immunosuppression and that the transplanted nerve graft is repopulated with autogenous or recipient SCs. Under conditions of CD40lCD40L co-stimulatory pathway blockade, there will likely exist a combination of autogenous and donor SCs within the transplanted nerve. If this hypothesis is correct, successful nerve regeneration in long nerve grafts will then require that tolerance or a permissive state must be established in the recipient through co-stimulatory pathway blockade to prevent rejection of the remaining SCs. If the entire allograft ultimately is replaced with autogenous SCs, then only temporary immunosuppression is required until all allograft SCs have been eliminated. Once the source of the SCs is clear, variables can then be manipulated to effect nerve regeneration.