OUR Current Strategies to Address the Remaining obstacles in LIFE-SUPPORTING RENAL XENOGRAFTS

Kazuhiko Yamada, M.D., PhD.
Transplantation Biology Research Center, MGH, Harvard Medical School
Center for Advanced Biomedical Science and Swine Research, Kagoshima University

Xenotransplantation offers the best near-term solution for the current limitation to the field of transplantation imposed by the shortage of human organs. In this presentation, I will discuss a potential cause of early renal graft loss and introduce our new strategy to prevent proteinuria in pig-to-baboon renal graft model. 

Over the past two decades, several laboratories, including our own, have developed genetically-modified swine lacking the gene encoding 1,3-galactosyltransferase (GalT-KO swine).  Use of these animals as donors has successfully overcome the previously devastating hypercube rejection of pig organs by primates due to natural anti-Gal antibodies.   We achieved survivals of recipients of life-supporting renal xenografts averaging 51 days, with some survivals as long as 83 days using a tolerance-inducing regimen with thymokidneys and 29 days without this strategy. In contrast, other groups have reported that GalTKO kidneys were all rejected within 3 weeks and most of grafts were rejected within 2 weeks. In order to identify the potential cause(s) of this difference, we performed xenotransplants using donors from two different sources of GalT-KO pigs. In addition, we have further investigated if the breeding process or environments are involved in the early graft loss. We have now obtained preliminary data indicating that the fortuitous absence of a latent porcine virus, such as porcine CMV, in our original donors is likely responsible for our extended graft survivals.  Such viruses are usually present in most, if not all, colonies of swine. Furthermore, our data indicate that this virus can be eliminated by delivery of potential donors by cesarean section suggesting that eradicating latent pig viruses from our inbred GaT-KO line is necessary for successful xenotransplantation.

One of major obstacles to long-term success in this model is the persistent development of proteinuria. In order to define the mechanism responsible for the development of proteinuria in our preclinical pig-to-baboon model, we have recently examined the role of SMPDL-3b and the effect of Rituximab treatment.  We found that Rituximab treatment prevented in vitro damage to pig podocytes as well as the early development of proteinuria following xenogeneic GalT-KO KTx in baboons. In both of these instances, treatment with Rituximab correlated inversely with the level of SMPDL-3b expression suggesting that the drug has a protective effect.   Although further optimization of protocol is required, these data provide intriguing clues to the mechanisms of post-transplant proteinuria in xenogeneic kidney transplantation and a potential strategy for its prevention