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.
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.
Authors: A B Adams; M M Durham; L Kean; N Shirasugi; J Ha; M A Williams; P A Rees; M C Cheung; S Mittelstaedt; A W Bingaman; D R Archer; T C Pearson; E K Waller; C P Larsen Journal: J Immunol Date: 2001-07-15 Impact factor: 5.422
Authors: Wilson Z Ray; Rahul Kasukurthi; Santosh S Kale; Katherine B Santosa; Daniel A Hunter; Philip Johnson; Ying Yan; Thalachallour Mohanakumar; Susan E Mackinnon; Thomas H Tung Journal: Muscle Nerve Date: 2011-01 Impact factor: 3.217
Authors: Wilson Z Ray; Rahul Kasukurthi; Esther M Papp; Amy M Moore; Andrew Yee; Daniel A Hunter; Nancy L Solowski; Thalachallour Mohanakumar; Susan E Mackinnon; Thomas H Tung Journal: J Neurosurg Date: 2010-02 Impact factor: 5.115