Short-term anti-CD40 ligand costimulatory blockade induces tolerance to peripheral nerve allografts, resulting in improved skeletal muscle function.
BACKGROUND
Reconstruction of long or multiple peripheral nerve defects with peripheral nerve autografts may not be possible due to insufficient quantities of donor nerve. There are promising preliminary data that nerve allografting has the potential to improve functional outcome and quality of life after devastating nerve injuries or large tumor resections. The authors previously demonstrated that blockade of the CD40/CD40 ligand costimulatory pathway, via anti-CD40 ligand monoclonal antibody (MR1) therapy, induces tolerance to peripheral nerve allografts in mice. In this study, the authors sought to correlate the immunomodulatory effects of MR1 treatment with functional muscle recovery after peripheral nerve allografting in the murine model.


METHODS
In the mouse hindlimb model, peroneal nerve isografts (C57BL/6 into C57BL/6) and allografts (BALB/c into C57BL/6) were utilized to reconstruct 0.8-cm peroneal nerve gaps. MR1 versus vehicle was administered on days 0, 1, and 2. At 60 days after transplantation, splenocyte production of interferon-gamma and interleukins 2, 4, and 5 were quantified using ELISPOT analysis, and in vitro maximum tetanic isometric force of the extensor digitorum longus muscle was measured.


RESULTS
At 60 days after transplantation, immunomodulation persisted in MR1-treated, allografted animals, as evidenced by significantly muted interferon-gamma, interleukin 4, and interleukin 2 splenocyte production. Functional extensor digitorum longus muscle recovery after nerve allografting and MR1 administration was improved due to the tolerance induced by MR1 compared with untreated allograft recipients.


CONCLUSIONS
Three-day inductive therapy with MR1 produces 60-day immunologic tolerance to peripheral nerve allografts, as evidenced by dramatic decreases in interferon-gamma, interleukin 4, and interleukin 2 production, and results in increased muscle force recovery. This work emphasizes the potential promise of CD40-CD40 ligand costimulatory blockade in reducing or eliminating peripheral nerve allograft rejection.
Brown
David L
DL
Section of Plastic Surgery, Department of Microbiology and Immunology, and Institute of Gerontology, University of Michigan, Ann Arbor, USA.
Bishop
D Keith
DK
Wood
Sherri Y
SY
Cederna
Paul S
PS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control; D006614:Hindlimb; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology; D009416:Nerve Regeneration; D019635:Neurosurgical Procedures; D010543:Peroneal Nerve / Q000293:injuries / Q000637:transplantation*; D020127:Recovery of Function; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007155:Immunologic Factors; D007376:Interleukin-2; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma