Gene Transfer of Antisense B7.1 Attenuates Acute Rejection Against Liver Allografts in Rats

Abstract

ABSTRACTObjective: Blockade of CD80-CD28 costimulatory pathway induces unresponsiveness of T cells to alloantigens and protects allografts against immune rejection. The aim of this study was to investigate whether downregulating the expression of B7.1 (CD80) in the donor livers by antisense B7.1 gene transfer could attenuate the acute immune rejection against liver allografts in rats. Methods: The liver grafts from 60 Dark Agouti rats were intraportally perfused with antisense B7.1 expression vector, before they were transplanted into Lewis rats. Empty vector pcDNA3 served as control to be perfused into livers of another group of 60 Dark Agouti rats. The orthotopic liver transplantation was performed. The rats were randomly sacrificed at scheduled time points to collect liver allografts, or monitored to record the survival rate. The livers were histologically examined to calculate Banff rejection activity index, or subjected to Western blot analysis or immunohistochemistry for examining the expression of B7.1, or counting CD4+ and CD8+ cells. Results: Antisense gene transfer resulted in markedly downregulation of B7.1 in the donor livers, attenuated acute immune rejection against liver allografts, prolonged the survival time of rats, and decreased the number of infiltrating CD4+ and CD8+ cells in livers. Conclusions: Blocking expression of B7.1 in liver by antisense gene therapy may represent a potential strategy to attenuate acute rejection against liver allografts.