Induction of donor-specific tolerance to rat nerve allografts with portal venous donor alloantigen and anti-ICAM-1/LFA-1 monoclonal antibodies

Background. Expendable autologous nerve available for repair of nerve injuries is limited. Cadaveric allografts could provide adequate nerve for grafting but are susceptible to rejection and currently require chronic systemic immunosuppression. Methods. Age-matched Buffalo (RT1(b)) rats randomly assigned to 7 experimental groups received either a Lewis (RT1) rat posterior tibial-sciatic nerve allograft or a Buffalo (RT1(b)) syngeneic isograft. Recipients were treated with anti-intercellular adhesion molecule- 1 (anti-ICAM-1) and anti-leukocyte function-associated antigen-1 (anti-LFA- 1) monoclonal antibodies (mAbs), intraportally administered ultraviolet B (UVB)-irradiated donor splenocytes, a combination of mAbs and UVB-irradiated donor splenocytes, or no immunosuppression. Results. Histologic, electrophysiologic, and functional evaluation of nerve allografts 8 weeks after transplantation revealed a synergistic improvement in nerve allograft regeneration when monoclonal antibodies were combined with UVB-irradiated donor splenocytes. In vitro immunologic assessment correlated with the in vivo allograft function by demonstrating a donor-specific suppression of the recipient's response in mixed lymphocyte culture (MLC), cytotoxic T lymphocyte assay (CTL), and reduced T cell interleukin-2 production in both the group receiving UVB-irradiated alloantigen alone and the group receiving a combination of UVB antigen and mAbs. Conclusions. The combined use of mAbs directed against ICAM-1 and LFA-1 adhesion molecules with intraportally administered UVB modified donor antigen prevents nerve allograft rejection and synergistically improves nerve regeneration.