When I received word of this wonderful honor, it caused me to reflect back on my career in transplantation. Over 45 years ago, my education in this field began with a three-year fellowship in immunopathology with an outstanding group of immunologists, including Frank Dixon, Joseph Feldman, Charlie Cochran, Joseph Vasquez, and Bill Weigle. That fellowship began in Pittsburgh, in 1960, and then as a team (Figure 1) we moved to La Jolla, California in 1961. My three years in basic immunology at the Scripps Clinic and Research Foundation resulted in a variety of studies, primarily with Feldman and Dixon, that elucidated the mechanisms of delayed-type hypersensitivity. We used labeled lymphocytes to demonstrate the cellular traffic accompanying this reaction. Our studies were reported in the Journal of Experimental Medicine, Immunology, New York Academy of Sciences, and the Lancet. In addition, our team defined the function of sensitized lymphocytes in homograft rejection along with the role of antibody in this response. Our investigations led to a quantitation of transplantation immunity as demonstrated in our series of experimental models.
In 1963, I returned to the University of California—San Francisco (UCSF), where I had completed medical school and my surgical residency. I joined the faculty as an assistant professor of surgery. At UCSF, I established the second clinical transplant program west of the Mississippi. My laboratory research was stimulated by Keith Reemtsma’s transplant of a nonhuman primate kidney from a chimpanzee into a human who survived for nine months. Reemtsma’s remarkable demonstration inspired a series of experiments in my laboratory with my first Ph.D. student, Robert Perper, on experimental kidney heterotransplantation. We rapidly realized that there are two types of heterotransplants: one between widely divergent species, and the other between closely related species. These types of transplants were subsequently called discordant and concordant. In animal models in my laboratory, we found that the concordant transplant performed by Reemtsma was not dissimilar from a homotransplant and was governed by cellular immunity. In contrast, we found that discordant transplants were subject to preformed antibodies that would result in hyperacute rejection. In addition, we showed that xenotransplant antibodies could be passively transferred to another animal of the same species.
During the four years that I was on the UCSF faculty, Bob Perper and I were impressed by the promise of antilymphocyte serum as a strong immunosuppressive agent, as demonstrated by Sir Michael Woodruff and others. The problem with antilymphocyte serum was that the preparation used by other investigators, namely Tom Starzl, was injected intramuscularly and caused severe pain, thus rendering it difficult to use in the clinical setting. Bob and I thought that if we could develop a purified form of antilymphocyte globulin (ALG) that could be administered intravenously, it could be added to the immunosuppressive regimen of prednisone and Imuran (commonly used at that time). These ALG studies began while I was in San Francisco.
In 1967, I was recruited to the University of Minnesota as professor and chairman of the Department of Surgery. I continued my interest in ALG and eventually developed an antiserum to cultured human lymphoblasts, with antibodies to both T and B cells. With this agent, we were able to improve the results of clinical transplantation, with a 15–20% increase in patient and graft survival rates. Over a 20-year period, 60,000 patients nationally and internationally were treated with Minnesota ALG until we were unfortunately and inappropriately placed on clinical hold by the U.S. Food and Drug Administration (FDA) in 1992.
The next major advance by our group in Minnesota was the world’s first clinical pancreas and kidney transplant in 1966, performed by Richard Lillehei and William Kelly. Subsequently, our pancreas transplant program under David Sutherland’s stewardship has grown to be the largest and most successful in the world, with over 2,000 pancreas transplants to date. In the 1970s, we performed the world’s first human islet allotransplant, as well as the first human islet autotransplant.
Given the excellent results achieved with the use of Minnesota ALG along with Imuran and prednisone, we began exploring the limits of kidney transplantation, looking beyond the “ideal” recipient age range of 15 to 45 years. As a result, we developed a very large program in pediatric kidney transplantation in which we have now performed over 900 kidney transplants in children, 49 under the age of 1 year and 220 under the age of 2 years. We also pushed the envelope in the opposite direction by transplanting numerous older patients up to the eighth decade of life. Moreover, we were among the first to perform kidney transplants in other high-risk patients, including those with enzymatic deficiency diseases, such as Fabry’s and Gaucher’s.
At the University of Minnesota, we are also extremely proud of our interest and work regarding infections in transplant patients. David Dunn, Richard Howard, and Dick Simmons pursued this area. In particular, Dunn showed that cytomegalovirus (CMV) infection could be treated and prevented with the use of ganciclovir and eventually valacyclovir. Also, Doug Hanto in our department demonstrated that Epstein-Barr virus was the pathogen responsible for posttransplant lymphoproliferative disorders.
In looking back over all of these accomplishments that I’ve participated in during my 45 years in transplantation, most rewarding of all was the development of our formal transplant training program. In 1969, most individuals involved in transplantation either were self-taught or simply observed other transplant surgeons. But by that year, we felt clinical organ transplantation had matured to a level that required a formal training program and this would be the best way to extend the miracle of transplantation to as many potential patients as possible. So that year, we began our University of Minnesota transplant training program. At first, it was a one-year transplant fellowship program, including six months as a donor fellow, responsible for vascular access and shunts and for donor operations (using living as well as deceased donors), and then six months as a recipient fellow, performing and assisting on all transplant operations. In 1985, with increasing pancreas, liver, and intestinal transplants, we extended our training program to 16 months, with four months each as a donor fellow, kidney recipient fellow, liver recipient fellow, and pancreas recipient fellow. In 2000, we again extended the transplant fellowship, this time to 24 months, with six months for each of the four rotations.
Over the past 35 years, we have now trained at the University of Minnesota 80 transplant fellows. One-third of them completed a one-year fellowship; the remaining two-thirds, a two-year fellowship. Table 1 lists the 80 transplant fellows we have now trained. Our transplant fellows (nearly half of our total number!) returned from around the globe in October 2003 to celebrate the 40th anniversary of transplantation at the University of Minnesota; that evening included a presentation of a lifetime achievement award to Dick Simmons and me.
The 80 transplant fellows who were trained at the University of Minnesota since 1969 have achieved much distinction, as shown by the following positions:
10 have become chairs in surgery; 21 directors of a transplant division; 44 practicing transplant surgeons; 7 presidents of the American Society of Transplant Surgeons; 1 president of The Transplantation Society; and 2 secretaries of The Transplantation Society.
In my presidential address to the American Society of Transplant Surgeons (ASTS) in 1977, I suggested to the membership that ASTS should require one year of formal training in transplantation, using the University of Minnesota model. In that way, the American Society of Transplant Surgeons would be responsible for our own training and not be under the American Board of Surgery, as has occurred with vascular surgery and other surgical subspecialties. My suggestion was approved by the membership. In 1980, I was appointed chairman of the ASTS education committee to evaluate and approve training programs in surgery, a position I held for 10 years. From that time forward, in order to be a member of ASTS, a surgeon must complete training in an ASTS-approved transplant training program.
The other suggestion that I made as ASTS president was that transplantation should not be a field of technical accomplishments by surgeons, but rather a true surgical science. To that end, I felt we should have at our annual meeting an invited basic science lecturer. I thought that no one was more appropriate for that first lecture than Sir Peter Medawar, who readily accepted. He is certainly the godfather of all of us in transplantation and was the first president of The Transplantation Society.
Unfortunately, in 1969, Sir Peter suffered a massive brain hemorrhage that resulted in the loss of the use of his left arm, left leg, and left eye. Yet his indomitable spirit prevailed and he was back to work in 1970. He was always with his lovely wife, Jean; as he stated, she was his “third leg, arm, and eye.” He continued to write and was extraordinarily active mentally, even supervising various research projects. As a true renaissance man, he continued his interests in opera, music, philosophy, and cricket. He also completed 11 books, the last of which was Memoirs of a Thinking Radish, which described what it is like to be physically handicapped and avoid self-pity—a book that should be read by all transplanters. In 1977, his ASTS lecture, as its first basic science lecturer, was entitled, “The Wider Implications of Transplantation Surgery” (Figure 2). In 1978, we asked Sir Peter to be a visiting professor at the University of Minnesota (Figure 3).
My Medawar Prize is a reflection of all the people in transplantation from whom I have learned so much: my mentors, colleagues, patients, fellows, residents, and finally students. I am truly honored to receive it in the name of my personal, professional, and academic hero—an honor I will cherish always.
Scripps Clinic and Research Foundation, 1961–1963
Najarian JS and Feldman JD. Passive transfer of tuberculin sensitivity by tritiated thymidine-labeled lymphoid cells. J Exp Med 1961; 114: 779.
Najarian JS and Feldman JD. The function of the sensitized lymphocyte in homograft rejection. Ann NY Acad Sci 1962; 99: 470.
Najarian JS and Feldman JD. Quantitation of transplantation immunity I. J Exp Med 1965; 121: 521.
University of California–San Francisco, 1963-1967
Perper RJ and Najarian JS. Experimental renal heterotransplantation. I. In widely divergent species. Transplantation 1966; 4: 377.
Perper RJ and Najarian JS. Experimental renal heterotransplantation. III. Passive transfer of transplantation immunity. Transplantation 1967; 5: 514.
Perper RJ and Najarian JS. Localization and quantitation of transplantation antibodies. J Immunol 1967; 99: 619.
Perper RJ, et al. A rapid method for purification of large quantities of antilymphocytic serum. Proc Soc Exp Biol Med 1967; 125: 575.
University of Minnesota, 1967–present
Najarian JS, et al. Antiserum to cultured human lymphoblasts. Ann Surg 1969; 170: 617.
Najarian JS and Simmons RL. The clinical use of antilymphocyte globulin. N Engl J Med 1971; 285: 158.
Lillehei RC, et al. Pancreatico-duodenal allotransplantation: Experimental and clinical experience. Ann Surg 1970; 172: 405.
Najarian JS, et al. Human islet transplantation: a preliminary report. Transplant Proc 1977; 1: 233.
High Risk Transplants
Najarian JS, et al. High-risk patients in renal transplantation. Transplant Proc 1977; 1: 107.
Najarian JS, et al. Renal transplantation in infants and children. Ann Surg 1971; 174: 583.
Tersigni R, et al. Renal transplantation in high risk patients older than sixty years. Am J Surg 1976; 131: 648.
Dunn DL and Najarian JS. Infectious complications in transplant surgery. In: Davis JM and Shires GT, eds. Principles and Management of Surgical Infections. Philadelphia, JB Lippincott, 1991: 425-464.
Dunn DL, et al. Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir. Transplantation 1991; 51: 98.
Hanto DW, et al. The Epstein-Barr virus in the pathogenesis of posttrransplant lymphoproliferative disorders. Surgery 1981; 90: 204.