BLOCKING OF ALPHA-1-BETA-1 INTEGRIN STRONGLY IMPROVES SURVIVAL OF HEPATOCYTES IN ALLOGENEIC TRANSPLANTATION

The survival rate of hepatocytes after allogeneic hepatocyte transplan tation (HTX) is low, possibly because of formation of intravascular he patocyte aggregates. The aim of this study was to determine the role o f integrins in intravascular aggregation and intraparenchymal survival of transplanted hepatocytes in a fully allogeneic rat model. First, t he expression profile of various integrins was determined on both isol ated hepatocytes in vitro and on hepatocyte aggregates in recipient li vers after intraporial transplantation of allogeneic hepatocytes. Next , the role of these integrins in hepatocyte aggregation was determined in an in vitro attachment assay on liver sections with function-block ing anti-integrin monoclonal antibodies (mAb). The results showed that anti-alpha 1 beta 1 integrin mAb significantly block hepatocyte attac hment to Vessel walls and liver parenchyma in vitro. Subsequently, the effect of preincubation of hepatocytes with anti-integrin mAb on thei r intravascular aggregation and on intraparenchymal survival was studi ed in an allogeneic HTX model. Preincubation with anti-leukocyte funct ion-associated antigen-1 alpha or anti-beta 2 mAb significantly inhibi ted intravascular hepatocyte aggregation, and anti-leukocyte function- associated antigen-1 alpha mAb enhanced intraparenchymal survival. Pre incubation with anti-alpha 1 or anti-beta 1 mAb did not inhibit aggreg ation but significantly improved survival from 2% to up to 45% at Day 2 after transplantation (p < 0.001). In conclusion, our results sugges t that the blocking of alpha 1 beta 1 integrin significantly improves survival of allotransplanted hepatocytes.