Ischemia reperfusion injury of transplanted organs represents a key pathogenic inflammatory process, which increases their allogenicity; subsequently augmenting the rate of acute and chronic rejection. However, mechanisms of increased allogenicity remain to be explored.

We have used OTI and OTII transgenic mice, which have T cell receptors specific for ovalbumin in the context of MHC class I and II respectively, to assess CD4 and CD8 T cells responses following transplantation of ischemic hearts from ovalbumin peptide transgenic mice (OVA). OVA hearts, subjected to 8 hours of cold ischemia and control OVA hearts (∼30 min of cold ischemia) were transplanted into OTI and OTII recipients. Median survival time (MST) for grafts in OTI recipients of ischemic and control OVA hearts were 10 and 9 days respectively. In contrast, accelerated rejection was observed in the CD8 transgenic recipients where MST for ischemic and control OVA cardiac allografts into OTII recipients were 33 vs. >50 days respectively.

We next carried out mechanistic experiments at different time points with the same model. Histology of OVA hearts showed marked increase in graft infiltration and tissue destruction as early as day 3 and progressed by day 6 in ischemic allografts compared to control. Interestingly, IHC revealed more CD8 infiltration in grafts subjected to prolonged ischemia; with a significant increase in CD8 interferon gamma (IFNg) producing cells in ischemic heart grafts at day 6, compared to control (27.77±2.46% vs. 15.9±1.8% respectively, P<0.05). At this early time point there was no increase in alloreactive IFNg producing cells in spleen between groups as studied with elispot.

To examine the effect of ischemia at the time of transplantation on rejection in a model of chronic allograft rejection, bm12 cardiac allografts exposed to 8hrs of ischemia were transplanted into B6 recipients. At 4 weeks post transplant we found severe graft infiltration and tissue destruction in the ischemic group, significantly more than control group indicating the effect of ischemia on induction of graft injury across a different conditions.

To summarize, our data indicate that donor ischemia leads to accelerated allograft rejection with more severe infiltration, acting through CD8+ IFNg production. Early activation of CD8 cells may point out their generation from existing pool of memory CD8 cells.

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