The influence of donor specific vertebral body derived bone marrow cell infusion on canine islet allograft survival without irradiation conditioning of the recipient.

Abstract

In recent studies in rodents, it was shown, that donor specific tolerance towards islet allografts without irradiation therapy of the recipient is induced by bone marrow cell infusion in combination with temporary immunosuppression. In the present study, the effect of donor specific bone marrow cell (DBMC) infusion at the time of intrahepatic islet allotransplantation without irradiation conditioning of the recipient was investigated in the canine model, paralleling ongoing clinical trials. It was observed, that unfractionated bone marrow cells given simultaneous to islet allografts led to higher frequencies of rejection periods and decreased islet allograft survival, when administered to recipients immunosuppressed with Cyclosporine A only. In contrast, an additional short inductive treatment of the recipient with an anti-dog-T-lymphocyte monoclonal antibody (5G2) abrogated the enhanced immunogenicity of the unfractionated bone marrow preparation, prolonging islet allograft survival with no rejection episodes observed during the immunosuppressive treatment with Cyclosporine. The composition of bone marrow cells might have contributed to the higher immunogenicity, since the percentage of MHC-class II antigen bearing cells is similar to man, but significantly higher than compared to rodents. It is therefore suggested, that further studies should encompass both timing of bone marrow cell infusion, appropriate immunosuppression and strategies to functionally inactivate mature MHC-class-II positive cells prior to DBMC infusion.