Unfortunately Mark had to miss the meeting due to an unanticipated conflict. John Potts stepped in and provided a very fine introduction to David and his lab. Following the introduction, David gave a stimulating presentation on his research tackling the challenges associated with inducing transplant tolerance. David introduced the talk by providing the key motivation for this work: Why induce transplantation tolerance? The answer is chronic rejection drug treatment related complications, ranging from infections to cancer to diabetes. For transplant patients, an enormous amount of drugs are taken per day that treat the side effects of chronic rejection. Little progress has been made to defeat chronic rejection. Rejection rates have not changed over time; approximately 5 to 7% of patients per year lose organs due to this currently inevitable consequence of transplantation.

David educated us on the mechanisms of tolerance including, clonal deletion and regulation – mechanisms that exist to prevent native autoimmunity. The idea of his research is to manipulate and use these inherent mechanisms induce tolerance to transplanted organs. David went on to detail the history of research on tolerance induction, starting with the fact that 5% of human beings develop autoimmunity sometime in their lives, and then describing the dizygotic bovine twins experiment of nature that shows that tolerance is indeed possible. He then educated us on mixed chimerism in lethally irradiated mice. When injected with T cell depleted bone marrow, organs can be transplanted without rejection chronic rejection and GVHD in these animals. Subsequently, similar findings were found with T cell depleted recipient mice, with monoclonal antibodies to CD4 and CD8 and low dose thymic irradiation. This recipe again led to healthy mixed chimeras with tolerance to transplanted organs.

Moving to primates, David showed results from monkeys who received low dose whole body radiation, thymic irradiation, Antithymocyte globulin (ATG) cyclosporine, kidney + bone marrow from donor, splenectomy + antibodies. Interestingly, although the monkeys lost their mixed chimerism in 60 days, it didn’t matter because kidneys remained tolerant.

Given these research findings, Sachs and team took this method of tolerance induction to patients. He described three studies 1) patients with refractive multiple myeloma and end-stage renal disease. Six patients were treated with HLA-matched bone marrow and kidney transplants All 6 patients were tolerant to their transplanted kidneys 10-15 years out. 2) For non-HLA matched multiple myeloma patients, the regimen was cyclophosphamide, ATG, and thymic irradiation, followed by bone marrow and kidney transplants. 4/5 patients remained off immunosuppression with tolerance to transplanted kidneys. 3) Because ATG can give rise to GVHD, Sachs and colleagues used MEDI-507 (Anti-CD2) + rituximab (Anti-CD20) instead to deplete T and B cells, respectively. This regimen worked nearly as well with 7/10 responders. David showed beautiful cases of successful kidney transplant recipients who underwent this regimen. The personal impact of this research was strikingly clear.

In addition to discussing tolerance, David also spoke about the lack of availability of organs and the importance of xenotransplantation. His lab has developed GAL and CD47 knockout swine and showed that with such animals, xenotransplanted swine skin can survive in the baboon. His message was clear about the slow but steady progress in the field of xenotransplantation and its importance to the field of transplantation in general. In summary, all witnessed an amazing presentation from the world’s leader in transplantation tolerance and xenotransplantation.