Effect of Inflammation on Costimulation Blockade‐Resistant Allograft Rejection

Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8+ T cells. These results indicated that some elements in addition to CD28‐ and CD40‐mediated costimulation provide stimulatory signals for the activation of donor‐specific CD8+ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation‐independent priming of CD8+ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c‐skin and adoptively transferred with syngeneic CD8+ T cells the same day or 50 days after transplantation. When blockade of CD28‐ and CD40‐mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well‐healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade‐resistant allograft rejection. Costimulation blockade failed to prevent acute graft‐infiltration of NK cells and increasing expression of intragraft IL‐12 and IL‐15. These factors may trigger the graft‐infiltration and priming of CD8+ T cells to induce costimulation blockade‐resistant allograft rejection.