Multiple costimulatory blockade in the peripheral nerve allograft

Neurol Res. 2010 Apr;32(3):332-6. doi: 10.1179/174313209X385635. Epub 2009 Jun 30.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Axotomy
  • CD28 Antigens / metabolism
  • CD40 Antigens / antagonists & inhibitors
  • 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 Regeneration / drug effects
  • Nerve Regeneration / immunology*
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / immunology*
  • Sciatic Nerve / transplantation*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Transplantation, Homologous

Substances

  • Antibodies, Monoclonal
  • Antigens, Differentiation, T-Lymphocyte
  • CD28 Antigens
  • CD40 Antigens
  • Icos protein, mouse
  • Immunoconjugates
  • Immunosuppressive Agents
  • Inducible T-Cell Co-Stimulator Protein
  • Abatacept