Multiple costimulatory blockade in the peripheral nerve allograft

• Published in: Neurological research (New York) 2010-04, Vol.32 (3), p.332-336
• Main Authors: Tai, Chau Y., Weber, Renata V., Mackinnon, Susan E., Tung, Thomas H.
• Format: Article
• Language: English
• Subjects: Abatacept; Animals; Antibodies, Monoclonal - pharmacology; Antigens, Differentiation, T-Lymphocyte - metabolism; Axotomy; CD28 Antigens - metabolism; CD40 Antigens - antagonists & inhibitors; COSTIMULATION BLOCKADE; Graft Rejection - immunology; Graft Rejection - prevention & control; Immunoconjugates - pharmacology; Immunosuppressive Agents - pharmacology; Inducible T-Cell Co-Stimulator Protein; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NERVE ALLOGRAFT; Nerve Regeneration - drug effects; Nerve Regeneration - immunology; NERVE TRANSPLANT; Sciatic Nerve - drug effects; Sciatic Nerve - immunology; Sciatic Nerve - transplantation; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transplantation, Homologous
• ISSN: 0161-6412; 1743-1328
• DOI: 10.1179/174313209X385635

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. Conclusion: 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.