"My career started in the laboratory with chickens, then mice, and then rabbits. And in every case, I became allergic to the animals that I was working with. But besides that, I really did want to apply what I learned in humans and finally did work out the right test, which turned out to be the micro-test. Because it was a small volume micro-test, it was possible for us to collaborate on an international basis. So tissue typing was established by international collaboration."
Paul Terasaki was Professor of Surgery Emeritus at the University of California Los Angles School of Medicine. He took his undergraduate studies at UCLA as well as work which led to both Masters and Doctorate degrees in zoology. Post-doctoral studies in London under the direction of Sir Peter Medawar gave Dr. Terasaki the impetus to make the science of immunology a life-long pursuit. Returning to California and appointed to the UCLA medical school faculty, Dr. Terasaki was among the first to study and define the molecular basis of the human rejection response; his laboratory developed tissue typing tests which could be widely applied at any transplant center. Broad understanding of the human leukocyte antigen (HLA) grew from these early efforts, which included close collaborative endeavors with founding members of the ASTS including Dr. Thomas Starzl. Dr. Terasaki founded the UCLA HLA laboratory and the UCLA Kidney Transplant Registry—at the time the most comprehensive data repository of kidney transplant outcomes in the world. He also founded One Lambda in 1984, a transplant immunology diagnostics company which now stretches to all parts of the world. Retiring from UCLA in 1999, Dr. Terasaki continued academic interests by establishing the Terasaki Foundation, which focuses on research related to cancer immunotherapy and the study of humoral immunity in transplantation. Dr. Terasaki was among the first Honorary Members of the ASTS. He was the recipient of many honors and awards including the UCLA Alumnus of the Year, the UCLA Medal, and a building at UCLA bearing his name, the Terasaki Life Sciences Building, which was endowed by his foundation. He passed away in January 2016.
Dr. Terasaki’s narrative is in his own words but has been edited for chronology and brevity.
Interviewer: Dr. Terasaki, thank you for coming. Can we start by asking how you became interested in transplantation and transplant immunology?
Dr. Terasaki: In 1956 I was lucky enough to get a job in the Department of Surgery at UCLA under Professor William Longmire. And at that time, we tried to find out why skin grafts in newborn chicks would survive. This led us to the work in tolerance and eventually to my fellowship with Sir Peter Medawar in London. And this experience really gave me the inspiration, the will to continue on in transplantation. After the post-doctoral fellowship with Medawar, I am not sure exactly why, I decided that tissue typing or typing the donors and recipients must be the way to get a successful transplant. In 1959 I started my own work at UCLA. First of all, I wanted to find a way to detect antibodies in transplanted patients, but at that time, I had no ability to work on human tissues. So, my first work in antibodies was done with chickens that had been skin grafted, and we could show that chickens would produce antibodies and reject their skin grafts.
Interviewer: Let’s go from there to the first clinical immunologic interventions that you were able to work upon.
Dr. Terasaki: So starting with the chickens, I went on to looking for antibodies in mice and rabbits. And finally in 1963, I was able to start work with human blood, which is what I originally wanted to do. And because I was a PhD and not able to get much blood from the blood bank, I was very limited in the amount of serum that I could get. Also the lymphocytes that we isolated from blood were very limited in number, so we were forced, you might say, to devise a micro-test. So, in 1964, because of that technique, we were able to use a tiny amount of serum, 1/1,000 of a milliliter for each test. But this helped us a lot because in transplanted patients, usually the amount of lymphocytes was very small in number and we really needed to have tests which used small numbers of cells.
Also, in 1964, I was lucky enough to have Dr. Fred Merkel visit UCLA and he put me in touch with Dr. Tom Starzl. From that point on, we studied all of the patients that Dr. Starzl was transplanting. So it was very fortunate that we developed our micro-test at almost the same time as Dr. Starzl’s first series of successful transplants.
In doing these tests and also in looking at other patients, we were able to foresee the need for a cross-matching test. Dr. William Goodwin at UCLA had done a brother-to-sister transplant, and he was surprised that the kidney immediately turned black upon transplant from hyperacute rejection. And when we tested the serum, we could see that the patient, because of her pregnancies, had antibodies, and these antibodies were directed exactly against the donor brother. And this was the first example of a positive cross-match from a failed transplant. Subsequently we did many, many more cases and found that whenever there is an antibody against the donor, that is a positive-cross-match, the kidney would immediately fail.
Interviewer: Could you describe the time when you began doing prospective cross-matching, and I think it was for multiple centers, UCLA, Colorado, others?
Dr. Terasaki: The cross-match data that we first really published was in the New England Journal in 1969. And we mentioned in the article that perhaps it might be malpractice to do a transplant without going ahead with this cross-match test. However it is interesting to see that for many, many years afterwards, we’ve encountered patients who have been transplanted across a positive cross-match and transplant failed. So it took a long time for the transplant community to really accept that data and to decide that they must do the test before the transplant to exclude donor-recipient pairs that were cross-match positive.
Next, with sibling donors, we established the idea that tissue typing and HLA matching would lead to better sibling donor kidney transplant success. We tried to also duplicate matching with deceased donors and this was much more difficult because for unrelated donors, the donor and recipient were almost invariably mismatched. So this is why we tried to develop a way to ship kidneys. Jeffrey Collins came to our laboratory, and since he was a surgeon, I put him on the project of trying to develop a solution so we could ship kidneys. And through the development of what is now known as the Collins Solution, we were able to ship kidneys to London, Tel Aviv, and Sydney successfully. And from that point on, kidneys have been shipped so that they could go to recipients who are better matched.
Interviewer: Part of the major contribution you have made has been your annual publication of Clinical Kidney Transplants. Could you tell us about the idea for the book and how it developed?
Dr. Terasaki: The UCLA transplant registry was started in 1970. We asked all of the transplant centers to send us data, and we were very happy to see that so many transplant surgeons worked with us collaboratively. The transplant registry was continued by a government-funded registry, the UNOS registry, in 1986. And from that time, the UNOS registry, which is a mandatory registry in the U.S., has kept track of transplants done in the United States. And we started to gather this kind of information and publish the results every year in our book called Clinical Kidney Transplants starting in 1985 and still continuing today. The registry work also depended on Dr. Michael Cecka. He has been involved in producing these yearly Clinical Transplants books for something like 20 years. Even today, he is a co-editor with me. Also in 1970, Gerhard Opelz from Stockholm came to our laboratory, and we were very lucky to have him. I think he published about a hundred papers in the ten years that he was with us. So he did much of the early analysis of transplants. Subsequently he went back to Heidelberg, Germany, and started the collaborative transplant registry which has continued to this day.
Interviewer: Tell us what some of your personal memories are.
Dr. Terasaki: I started my work in the UCLA Department of Surgery. I believe that Dr. William Longmire, the Chairman, was interested in transplant. He did interesting work with skin grafts from many donors onto one patient and none of the skin grafts survived; he was one of the first to suspect that there must be many tissue types in the world.
But through the Department of Surgery, I was able to meet surgeons at other universities, and the surgeon who influenced my work the most was Dr. Tom Starzl, because he was the first to try to apply tissue typing to the transplants. And he supported our efforts, quite strongly. However, he was the first also to see that many of the mismatched transplants succeeded, and therefore, to some extent, tissue typing wasn’t working.
So oftentimes he would say the liver transplant that he developed was because of the failure of tissue typing. Now he felt free to transplant livers from any donor, because, of course, it’s very hard to match liver transplant donors and recipients. So he would match them on the basis of size, mostly, to donor and the recipient.
Dr. Starzl, even though he didn’t accept the results of tissue typing, has been a strong supporter. For example, he helped us to obtain the UNOS registry contract, which then helped us to continue our work in analyzing the transplants.
Interviewer: What was Paul Terasaki’s day like in the late 1970s, early 1980s?
Dr. Terasaki: When I started my work in earnest, most of the time I spent something like 18 hours a day in the laboratory, trying to figure out how to do tissue typing, how to get the right cells, and how to measure the effect of antibodies. So even though I had four children, I was not a very good father since I rarely went to my children’s events. I was lucky that my wife took care of all of their needs.
Interviewer: I know you started out as a bench investigator.
Dr. Terasaki: Yes. My career started in the laboratory with chickens, then mice, and then rabbits. And in every case, I became allergic to the animals that I was working with. (Laughs) But besides that, I really did want to apply what I learned in humans and finally did work out the right test, which turned out to be the micro-test. Because it was a small volume micro-test, it was possible for us to collaborate on an international basis. So tissue typing was established by international collaboration.
Many laboratories throughout the world, Holland, France, Germany, many investigators were able to cooperate with each other by exchanging, for example, one milliliter of serum, which is enough to do 1,000 tests. And it was through this kind of collaboration that the HLA system was established, and we now know that there are 2,000 HLA types that exist in the human race.
Interviewer: How many HLA types did you start with in humans? What was the human leukocyte antigen and how did that come about?
Dr. Terasaki: When we started the tissue typing, the first international workshop was concerned with what is the method? What is the best way to do the test? There were maybe five different tests that were proposed in the first workshop organized by Dr. Bernard Amos at Duke. And then the second workshop was organized by Dr. Van Root in Holland in 1965. There we started to see what tissue types exist, and I would say that something like 10 tissue types were recognized. And in 1967, we began to see that these types that were identified by antibodies were controlled by a single genetic locus, which we called the HLA locus.
In 1970, the fourth workshop, we all agreed the micro-test would be the international standard. And with this international standard, we then were able to find more and more tissue types. In 1970, we had something like 20 or 30 tissue types. And from then, we’ve had continuous workshops, international workshops every two to four years, and today we are working on the sixteenth international workshop.
In the 1970s, the biggest event for me was The Hague International Transplant meeting where we showed that mismatched transplants could function well. And because of that, many surgeons decided that tissue typing was not useful. Yet, we wanted to show that at least well-matched transplants would work better, and I think that that part of our work has been confirmed. So, thereafter, UNOS established a national file of recipients needing zero-mismatch kidney transplants. More than 20,000 zero-mismatch transplants have been done to date, and these kidneys have had the best results.
However, there are many mismatched patients who succeed. For example, in heart transplants, where it is not possible to do good matching, there is about a 90% success rate at one year. And this is true for livers. But if you look at 10 years, the mismatched organ graft survival is 50%, even though they all functioned out to one year. So we have spent most of our time recently trying to figure out if there is a way to change that. And it was interesting to find that some patients who are mismatched do not react, whereas some patients who are mismatched produce HLA antibodies against the donor. And these HLA antibodies then cause the chronic rejection that we see in many of these organs. So today we hope that by removing these antibodies, we will be able to finally solve the chronic rejection problem.
Interviewer: Give us a sense of how you have interacted with ASTS over the course of the many years, perhaps your first paper at the ASTS?
Dr. Terasaki: During my work in transplantation, we had many meetings. In the U.S., the American Society of Transplant Surgeons and also the American Society of Transplant Physicians were formed. I was not directly involved in either of these associations, although I attended meetings of the American Society of Transplant Surgeons. I became, I think, one of the first honorary members of the ASTS, since I was not myself a surgeon.
Interviewer: What is Paul Terasaki doing today? What’s your day like in Los Angeles now?
Dr. Terasaki: When I was 70 years old, I retired from UCLA and I started a foundation, where I have about 15 people. We have spent these last 10 years trying to find out what is the cause of chronic organ transplant failure. I don’t work as long hours as I did. But today I work you might say a “normal eight-hour day” and I don’t work on weekends anymore.
One of the projects that I have been working on the last three years has been to see if we could take another approach to tolerance. And in India, I was fortunate enough to meet Dr. Trivedi, who was already doing something that I wanted to do, and that is clonal deletion. What’s done is a patient gets a blood transfusion from the donor. And then the responding cells are killed by drugs or irradiation, and the patient is transplanted with no drugs. About 100 patients have been treated in India, and we have 25 patients today who are tolerant. That means that they have been transplanted with no conventional immunosuppressants, and the longest survival is now two-and-a-half years. So we believe that possibly in the future, clonal deletion will be one of the ways to obtain tolerance to the transplant.
I have considered myself very fortunate as my work in tissue typing corresponded to the time in which the whole field of transplantation started and developed. Histocompatibility and transplantation really took hold in the last 50 years. And I feel privileged to have been able to work during that time.
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