FK506 and anti-CD40 ligand in peripheral nerve allotransplantation

Purpose: Immunomodulatory agents are often combined in organ transplantation to minimize toxicity and enhance therapeutic effect. We hypothesized that combining low-dose FK506 with anti-CD40 Ligand (anti-CD40L mAb) would enhance regeneration through peripheral nerve allografts while preserving immune unresponsiveness. Methods: Eighty Balb/cJ mice underwent tibial nerve grafting and were randomized to 10 groups treated with combinations of anti-CD40L mAb therapy, low-dose FK506 (0.5 mg/kg/day), high-dose FK506 (2 mg/kg/day), and high-dose cyclosporine (25 mg/kg/day). At 3 weeks, histomorphometry and cytokine secretion assays were performed. Results: Animals receiving low-dose FK506 with anti-CD40L mAb exhibited robust nerve regeneration comparable to the isograft and high-dose FK506 allograft groups. Nerve density was significantly increased in the low-dose FK506 with anti-CD40L mAb group compared to animals receiving anti-CD40L mAb alone (p < 0.05). Combining anti-CD40L mAb with high dose cyclosporine decreased nerve fiber counts, nerve density, and percent nerve (p < 0.05). Interferon-γ production was markedly elevated in untreated allografts compared to all other treatment groups (p < 0.05). Cytokine secretion was intermediate in the low-dose FK506 alone group and suppressed in all remaining groups. Conclusion: When combined with anti-CD40L mAb, low-dose FK506 enhances nerve regeneration without disrupting immune unresponsiveness.