Affiliations: Department of Otolaryngology - Head & Neck
Surgery, Washington University School of Medicine, St. Louis, Missouri,
USA | Division of Plastic and Reconstructive Surgery,
Department of Surgery, Washington University School of Medicine, St. Louis,
Missouri, USA | Departments of Surgery, Pathology, and Immunology,
Washington University School of Medicine, St. Louis, Missouri, USA
Note: [] Corresponding author: Susan E. Mackinnon, M.D., Shoenberg
Professor and Chief, Division of Plastic Surgery, 660 South Euclid, Campus Box
8238, St. Louis, MO 63110, USA. Tel.: +1 314 362 4586; Fax: +1 314 362 4536;
E-mail: mackinnons@msnotes.wustl.edu
Abstract: 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.
