FK506 and anti-CD40 ligand in peripheral nerve allotransplantation.
OBJECTIVE
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-gamma 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.


CONCLUSIONS
When combined with anti-CD40L mAb, low-dose FK506 enhances nerve regeneration without disrupting immune unresponsiveness.
Brenner
Michael J
MJ
Department of Otolaryngology - Head & Neck Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Mackinnon
Susan E
SE
Rickman
Susan R
SR
Jaramillo
Andrés
A
Tung
Thomas H H
TH
Hunter
Daniel A
DA
Mohanakumar
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D023201:CD40 Ligand / Q000276:immunology*; D003584:Cytological Techniques / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009412:Nerve Fibers / Q000187:drug effects / Q000637:transplantation; D009416:Nerve Regeneration / Q000187:drug effects*; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use; D013979:Tibial Nerve / Q000187:drug effects / Q000637:transplantation* / Q000648:ultrastructure; D014184:Transplantation, Homologous / Q000379:methods
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D016559:Tacrolimus