Inhibition of Endogenous Memory CD8 T Cell Infiltration into Cardiac Allografts Subjected to Prolonged Cold Ischemic Storage is Required to Promote Long-Term Graft Survival Naoki Kohei, Hidetoshi

Abstract

Abstract Endogenous memory CD8 T cells infiltrate MHC-mismatched cardiac allografts and produce IFN-γ in response to donor class I MHC within 24 hrs after graft reperfusion in mice. We have reported that prolonged cold ischemic graft storage (CIS) provokes intense inflammation within hours after allograft reperfusion and promotes CTLA-4Ig-resistant endogenous memory CD8 T cell rejection of the allograft by day 28 post-transplant (whereas CTLA-4Ig prolongs survival of allografts subjected to minimal CIS > day 60). We tested strategies inhibiting endogenous memory CD8 T cell infiltration into cardiac allografts subjected to prolonged CIS to promote long-term allograft survival. Peri-transplant anti-LFA-1 mAb and anti-CD154 mAb treatment of recipients of allografts subjected to minimal CIS prolonged survival of 60% of allograft > 100 days. In contrast, this treatment prolonged only 20% of allografts subjected to prolonged CIS beyond day 80 post-transplant, with rejection accompanied by the appearance of high titers of donor-specific antibody (DSA >10,000 vs. <100 in long-term survivors). Use of a new regimen: peri-transplant recipient treatment with anti-LFA-1 mAb, anti-TNFa mAb, and anti-CD154 mAb plus additional doses of anti-CD154 mAb on days 14 and 16 post-transplant promoted long-term survival of 60% allografts subjected to prolonged CIS past day 100 post-transplant. Recipients with surviving allografts accepted donor skin allografts, but rejected third-party skin allografts. These studies indicate long-term survival of allografts subjected to prolonged CIS by using strategies that include reagents inhibiting endogenous memory CD8 T cell infiltration into the allografts and reagents that inhibit the production of DSA.