Allo- et Xenotransplantation
Leader : Pr Leo Bühler
Islet transplantation is a promising approach for treatment of diabetes. Facing the shortage of allogeneic organ donors and the increasing number of patients on waiting lists, xenotransplantation of animal organs or cells to humans could play an important role in the solution of this problem. Currently, organ or cellular xenografts have not achieved long-term survival in pre-clinical or clinical models and rejection mechanisms are still incompletely understood.
Costimulatory blockade has been shown to efficiently block allograft rejection in small and large animal models of organ and islet allotransplantation . Only a few reports have investigated the ability of costimulatory blockade to prevent xenograft rejection. Anti-CD154 mAb is able to delay T cell-mediated rejection of porcine skin graft in mice and also to block T cell-dependent antibody production in the pig–to-baboon model.
Consequently, costimulatory blockade is a promising approach to allow long-term survival of cellular xenografts. The purpose of our project was to determine the role of costimulatory pathway in the rejection process of concordant and discordant islet xenografts.
The preliminary results have shown that combination of rapamycin and anti-CD154 mAb allowed long-term graft survival of concordant islet xenografts, while combination of CD154 mAb and CTLA4Ig was required to induce long-term survival of discordant islet xenografts. These results suggest that clinically applicable therapies are able to induce stable peripheral tolerance to cellular xenografts
Figure: Long-term function of islet xenografts.
Rat islets were transplanted to diabetic mice under the kidney capsule, treated during 15 days by a combination of rapamycin and anti-CD154 monoclonal antibody. At 120 days, the mice remained normoglycemic kidney biopsies demonstrated well preserved islets staining positive for insulin, without signs of rejection. A state of immunotolerance was induced. (Left: hematoxilin-eosin, x100; right: immunostaining for insulin,x100)