Comparison of regeneration across nerve allografts with temporary or continuous cyclosporin A immunosuppression

Abstract

The efficacy of short-term immunosuppression in a nerve allograft model was examined by comparing regeneration across peripheral nerve allografts with either temporary (12 weeks) or continuous (30 weeks) cyclosporin A treatment. One-hundred fifty Lewis rats received 2-cm nerve grafts from allogeneic ACI or syngeneic Lewis rat donors and were allocated to the following groups: allogeneic grafts and continuous cyclosporin A, with 18 weeks (20 rats) or 30 weeks (20 rats) of survival after graft placement; allogeneic grafts and temporary cyclosporin A, with 12 weeks (10 rats), 18 weeks (20 rats), or 30 weeks (20 rats) of survival; and control rats with allogeneic and syngeneic grafts, no cyclosporin A, with 12, 18, or 30 weeks (10 rats each) of survival. Functional regeneration across the nerve grafts was serially assessed with walking-track analysis. Endpoint evaluations included electrophysiological, histological, and morphometric studies. Both walking-track and electrophysiological function reached a plateau at a significantly worse level in nonimmunosuppressed allograft recipients than in syngeneic or treated allograft recipients. The group with temporary therapy experienced significant worsening in both motor and electrophysiological function at Week 18, 6 weeks after cyclosporin A withdrawal, compared to the group with continuous treatment. At Week 30, motor and electrophysiological function in the temporary-treatment group recovered to levels similar to those of the syngeneic and continuous cyclosporin A groups. Histological assessment of the graft segments from the temporary cyclosporin A group at 18 weeks showed evidence of rejection, with mononuclear cell infiltration and demyelination; morphometric evaluation demonstrated significantly decreased numbers of nerve fibers in the distal host segment. These histological and morphometric changes were no longer present in the nerves from the temporarily immunosuppressed rats at Week 30. Withdrawal of immunosuppression after successful regeneration through nerve allografts results in short-term graft rejection. Eventual restoration of graft histological and function parameters is comparable to continuously immunosuppressed rats. Temporary immunosuppression of nerve allograft recipients is feasible.