Multiple costimulatory blockade in the peripheral nerve allograft.
BACKGROUND
In the nerve allograft model, costimulation blockade has permitted good regeneration but is still inferior to the nerve isograft. We hypothesize that a short course of multiple costimulatory pathway blockade will be more effective in inhibiting the redundancy of the immune response and improve nerve regeneration through the nerve allograft.


METHODS
The murine sciatic nerve allograft model was used to reconstruct a 1 cm sciatic nerve gap. Treatment consisted of the inhibition of the CD40, CD28/B7 and ICOS pathways and was compared with only single or double costimulation blockade. Assessment methods included quantitative histomorphometry and ELISPOT assay to quantify the host immune response after 3 weeks post-operatively.


RESULTS
Triple costimulation blockade permitted regeneration through the nerve allograft that was equivalent to the nerve isograft. A short course of three doses was more effective than a single dose for all combinations tested. ELISPOT assay demonstrated minimal in vitro immune response with a short course of double or triple pathway-blocking agents.


CONCLUSIONS
Costimulation blockade, especially with the simultaneous inhibition of multiple pathways, remains a promising strategy to promote regeneration through the peripheral nerve allograft, and may be uniquely suited to the temporary immunosuppressive requirements of the peripheral nerve allograft.
Tai
Chau Y
CY
Division of Plastics and Orthopedics, Kern Medical Center, CA, USA.
Weber
Renata V
RV
Mackinnon
Susan E
SE
Tung
Thomas H
TH
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D019771:Axotomy; D018106:CD28 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects / Q000276:immunology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D019013:CD40 Antigens; C556694:Icos protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D060889:Inducible T-Cell Co-Stimulator Protein; D000069594:Abatacept