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The AJT Report

2015; Elsevier BV; Volume: 15; Issue: 11 Linguagem: Inglês

10.1111/ajt.13553

1600-6143

Sue Pondrom,

Organ and Tissue Transplantation Research

This month, we speak with Sir Roy Calne and Terry Strom, both honored as “innovators in transplantation” at the 2015 American Transplant Congress, about their careers and the future of transplantation. This month, we speak with Sir Roy Calne and Terry Strom, both honored as “innovators in transplantation” at the 2015 American Transplant Congress, about their careers and the future of transplantation. THE VISIONARIES Two transplant innovators discuss the specialty THIS MONTH, we speak with Sir Roy Calne and Dr. Terry Strom, both honored as “Innovators in Transplantation” at the 2015 American Transplant Congress, about their contributions to transplantation, the challenges they’ve faced during their careers and what they see for the future of the specialty. The insights of Sir Roy Calne “Being told you can’t do something is a strong stimulus to do it,” Sir Roy Calne, FRCP, FRCS, FRS, said at the American Transplant Congress May 6, 2015, in Philadelphia. He remembered one of his first cases while in training. He was told to make the young patient with kidney failure as comfortable as possible because he would die in two weeks. “I was very upset about this because I was fond of the patient. I asked if he could have a kidney graft, and they said no. When I asked why not, they said it can’t be done.” Sir Roy Calne As Sir Roy’s stunning career illustrates, “It Can’t be Done: Believing in the Impossible” was the title of his American Transplant Congress presentation as an “Innovator in Transplantation.” Sir Roy performed the first liver transplant in Europe in 1968; the world’s first liver, heart and lung transplant in 1987; the first intestinal transplant in the United Kingdom in 1992; and the first successful combined stomach, intestine, pancreas, liver and kidney cluster transplant in 1994. In addition to these numerous technical accomplishments, much of his work has centered on the improvement of immunosuppression techniques and the introduction of novel immunosuppressive drugs, including the introduction of the first approach to drug-induced immunosuppression in transplantation. Dr. Calne, who is an emeritus professor of surgery at the University of Cambridge, England, recently answered a few questions from “The AJT Report.” AJT: What or who most influenced your work? DR. CALNE: I was most influenced by Peter Medawar, who was an inspirational mentor and a brilliant scientist. I am also especially indebted to John Hopewell, my surgical boss at the Royal Free Hospital in London, and Professor David Slome, who encouraged me in my first work of immunosuppression in 1959 at the Royal College of Surgeons Research Institute where he was the director. Q: How have you managed to be at the forefront of so many breakthroughs in transplantation: the first description of immunosuppression, the first transplant of the liver (and other organs) in Europe and the United Kingdom, the translation of cyclosporine to the clinic, the resurrection of rapamycin, the first humanized antibody (Campath)? A: These questions are difficult to answer but I suppose I started my research early in 1959 and was single-minded in trying to prove the pessimists wrong who declared that all transplantation was not possible. This pattern came to be repeated in the various phases that you mention. Q: What has been your greatest contribution to the field? A: My demonstration of drug-induced immunosuppression for organ grafting published in The Lancet in 1961 is probably my most important contribution, as it started to open the door into a new and important type of medical treatment. Q: What have been the biggest contributions of others to the field? A: I would regard the work of Medawar’s group as the most important in transplantation immunology; it began to unravel the mechanisms of graft rejection and also showed a way in which this could be overcome, albeit in the specialized field of immunological tolerance. Q: What was the most challenging period in your work life? A: The most challenging period in my work was starting the liver transplant program in England. Although we were successful with the technique in animals, when we moved to the clinic the only patients who were referred to us had advanced disease and were near death. We had to wait for cardiac arrest before removing the donor organ so the liver to be transplanted had already been damaged before the transplant operation began. This was before the identification and acceptance of “brain death.” Q: How would you compare or contrast yourself to Dr. Tom Starzl? A: It is very difficult to make a direct comparison with Tom Starzl. He is the hardest worker I have ever come across and drove himself day and night, focused on a specific challenge and sometimes more than one at a time. In many ways our work was similar. We both trained many young surgeons from countries all over the world. For about 10 years his unit and ours were the only two performing clinical liver transplants. Over the years we have met many times, compared notes and tried to plan for ways of improving results. Q: What do you believe will be the next big breakthrough in tolerance? A: I am reluctant to anticipate the next big advance. Perhaps the understanding of the mechanisms I have put forward on tolerance may lead to many patients obtaining good results with far lower doses of toxic immunosuppression, which I call “prope,” or almost tolerance. Also, I can imagine that new agents will be discovered, some small molecules and others biological, which will liberate patients from the danger of nephrotoxicity from calcineurin inhibitors and the excessive side effects of corticosteroids. Dr. Terry Strom discusses his career “It can be very difficult to achieve tolerance in states where noxious inflammation is going around,” Terry Strom, MD, told an audience at the May 6, 2015, American Transplant Congress session “Innovators in Transplantation.” Terry Strom, MD Dr. Strom is the scientific director of the Transplant Research Center at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston. His laboratory focuses on molecular aspects of T cell biology, transplantation rejection and tolerance. When he was awarded the 2011 Alfred Newton Richards Award from the International Society of Nephrology, presenters praised his groundbreaking work in understanding the basic mechanisms underlying immunosuppressive agents, which has led to the design of new therapeutics and the development of immune-tolerance therapies for patient care. Dr. Strom recently answered questions from “The AJT Report.” AJT: What or who has most influenced your work? DR. STROM: While in medical school in Chicago, I was inspired by a group of nephrologists, led by Victor Pollak, and pathologists who developed percutaneous renal biopsies as a means to diagnose and track the progression of renal diseases. I was fascinated by their ongoing studies of lupus nephritis. Peter Medawar visited the campus during this period and lectured on the potential for using treatment with antilymphocyte globulin (ALG) in transplantation. I wrote Medawar and asked about the potential for treating autoimmune diseases with ALG, especially a mouse model of lupus nephritis. Amazingly, he wrote back, encouraged me and secured investigators in another university to lend assistance. His generous aid led to a project that changed the direction of my career. In time, I became a renal fellow at the Peter Bent Brigham Hospital and was blessed to study with John Merrill and his colleagues, including Joe Murray, who pioneered renal transplantation. Their determination integrating immunology into the practice of renal transplantation has shaped my career. Q: How has your research been translated into clinical care? A: The opportunity to mix clinical practice and research has afforded me a number of opportunities to make an impact on clinical practice. The first such opportunity came when Nick Tilney and I became the surgical and medical directors of the renal transplant program at PBBH [Peter Bent Brigham Hospital] and took a fresh look at deceased donor renal transplant outcomes in the 1970s. We realized that the then standard of care (to repeat over and over again intense antirejection treatment) was inappropriate as evidenced by outcomes and renal biopsies. We ended this practice and began the first use of peritransplant antimicrobial prophylaxis. In the deceased donor setting, our mortality was reduced by 60% without an impact on one-year graft survival. Our research in mouse transplant models led to the development of anti-CD25 (IL2R) mAb treatment in the clinic, and we participated in the initial trials. We were the first to use transcriptional profiling to hunt for clues to the mechanisms of rejection and biomarkers for rejection. While the hunt for universally useful biomarkers is ongoing, the progress in the field is heartening. Finally, our hypotheses that certain attributes of sterile inflammation that accompany ischemia/reperfusion injury or the death of cell transplants prior to neovascularization contribute to rejection and difficulty in achieving tolerance are currently undergoing clinical trial. I am characteristically optimistic. Q: What has been the biggest highlight of your career, to date? A: I am most proud of the American Society of Transplantation Mentorship Award that reflects the success of my trainees in transplantation and immunology. Q: What are you and your team working on now? A: We are studying the composition of sterile inflammation and its control. We believe that transplant tolerance will not be readily achieved until we learn how to rapidly induce an immunoregulatory and cytoprotective texture in the sterile inflammatory response characteristic of brain death, ischemia perfusion injury and the hypoxic death of cell transplants prior to neovascularization. Why? Immunoregulatory cells, including but not limited to regulatory T cells, do not maintain a potent immunoregulatory phenotype in many inflamed environments. Q: What will be the next big breakthrough in tolerance from you or others? A: As full donor hematopoietic chimerism seems out of reach at this moment, we sense that wedding potent means of inducing mixed chimerism with control of sterile inflammation will produce a means to achieve marked depletion of donor-reactive T cells while maximizing the contributions of the growing family of well-characterized immunoregulatory cells to produce transplant tolerance.