PROLONGATION OF IN VIVO MOUSE ISLET ALLOGRAFT SURVIVAL BY MODULATION OF MHC CLASS I ANTIGENs

Abstract

Major histocompatibility complex class I-deficient islets from beta-2 microglobulin-deficient mice have been shown to have prolonged in vivo islet allograft survival. Additionally in vitro studies using the mixed lymphocyte islet coculture system have demonstrated a reduction in cytotoxic T lymphocyte activity against alloislets that have been pretreated with an antibody directed against MHC class I antigen. The clinical applicability of these findings are examined in this study, which evaluates the ability of MHC class I blocking antibody to prevent the in vivo destruction of alloislets. Recipients of allogeneic islet transplants treated with phosphate-buffered saline or control F(ab')₂ fragments rejected the transplanted alloislets in median times of 11.5 days and 11 days, respectively. Recipient mice treated with a monoclonal antibody or F(ab')₂ fragments specific to the donor MHC class I antigen had significant prolongation in allograft survival (median allograft survival for both groups was 21 days) when compared with mice treated with PBS or control F(ab')₂ fragment. These results demonstrate that treating recipients of alloislets with donor-specific MHC class I monoclonal antibody or the respective F(ab')₂ fragments prolongs islet allograft survival. This confirms the importance of MHC class I antigen in the rejection of pancreatic islet allografts and suggests that blocking different domains on the MHC class I molecule could be used therapeutically in the protection of allografts from the immune system.