Intestinal Ischemia Reperfusion and Lipopolysaccharide Transform a Tolerogenic Signal into a Sensitizing Signal and Trigger Rejection

Abstract

After intestinal transplantation (ITx), rejection is vigorous and tolerance is difficult to achieve. A possible reason for this phenomenon is that ITx and ischemia reperfusion injury are accompanied by translocation of lipopolysaccharide (LPS), a "danger" signal capable of activating adaptive alloimmunity against Tx antigens. To study that, we used our previously described rat model where donor-specific blood transfusion (DSBT) induces tolerance to fully mismatched heart allografts. In this model, control grafts are rejected within 9 days, whereas 100% of DSBT pretreated grafts survive long term. In contrast with heart Tx, an identical DSBT protocol failed to induce tolerance in 57% of recipients after ITx (P<0.05). We hypothesized that DSBT promotes tolerance to heart but not intestinal allografts (partly) because of ischemia/reperfusion injury and LPS translocation associated with ITx. We tested this hypothesis by adding to DSBT an inflammatory signal in the form of a remote intestinal/ischemia reperfusion injury or by administrating 0.1 mg of LPS. These maneuvers (partially) abrogated tolerance induction (P<0.05). Addition of a danger signal (remote intestinal ischemia/reperfusion) transforms a tolerogenic signal (DSBT) into a sensitizing signal and may lead to graft rejection. This effect is mediated in part by LPS. This may, partly, account for the high rejection rate and the difficulty to induce graft acceptance after ITx.