Blocking of alpha 1 beta 1 integrin strongly improves survival of hepatocytes in allogeneic transplantation.

The survival rate of hepatocytes after allogeneic hepatocyte transplatation (HTX) is low, possibly because of formation of intravascular hepatocyte aggregates. The aim of this study was to determine the role of integrins in intravascular aggregation and intraparenchymal survival of transplanted hepatocytes in a fully allogeneic rat model. First, the expression profile of various integrins was determined on both isolated hepatocytes in vitro and on hepatocyte aggregates in recipient livers after intraportal 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-blocking anti-integrin monoclonal antibodies (mAb). The results showed that anti-alpha 1 beta 1 integrin mAb significantly block hepatocyte attachment to vessel walls and liver parenchyma in vitro. Subsequently, the effect of preincubation of hepatocytes with anti-integrin mAb on their intravascular aggregation and on intraparenchymal survival was studied in an allogeneic HTX model. Preincubation with anti-leukocyte function-associated antigen-1 alpha or anti-beta 2 mAb significantly intravascular hepatocyte aggregation, and anti-leukocyte function-associated antigen-1 alpha mAb enhanced intraparenchymal survival. Preincubation with anti-alpha 1 or anti-beta 1 mAb did not inhibit aggregation but significantly improved survival from 2% to up to 45% at Day 2 after transplantation (p < 0.001). In conclusion, our results suggest that the blocking of alpha 1 beta 1 integrin significantly improves survival of allotransplanted hepatocytes.