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Robert S. Schwartz, MD

The Dawn of Immunosuppression

Schwartz, Robert S., MD

doi: 10.1097/TP.0000000000000987
In View: People in Transplantation
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Transplantation: What event or individual led you into the field of immunology?

RS: In 1956, I was a 28-year-old medical resident at the Yale-New Haven Medical Center. Like many of my peers, my plans for the future were vague. I had published 2 case reports, 1 about an electrocardiographic phenomenon called electrical alternans; the other, about a case of leukopenia, which turned me towards hematology, but I wasn't ready to make a commitment. In any case, I didn't know how to proceed after my residency.

In the fall of 1956, William Dameshek, a prominent hematologist, came down from the New England Medical Center in Boston to conduct medical grand rounds. His enthusiasm and the brilliant way he clarified a complex topic impressed me considerably. I decided to apply for a position in his hematology training program. This choice would prove auspicious for both Dameshek and me.

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Transplantation: What was the most formative experience of your career?

RS: When I arrived at the New England Medical Center (now Tufts Medical Center) in 1957, bone marrow transplantation for the treatment of chemotherapy-resistant leukemia was a prominent theme in the hematology unit. Motivating the project were reports of the cure of leukemia in mice with lethal total body radiation, followed by the rescue of the animal's hematopoietic system with syngeneic marrow from a normal mouse.1 Also, Main and Prehn had found that, after receiving lethal radiation, mice accepted skin allografts from the “rescue” animal.2 In a similar experiment, John Mannick, a surgical resident at the Peter Bent Brigham Hospital, reported that anephric beagle dogs subjected to whole body radiation accepted a renal allograft from the donor of the “rescue” marrow.3 These results raised the stakes on the proposition that leukemia in humans could be cured by whole body radiation and hematopoietic cell rescue—the radiation would kill leukemia cells and prevent rejection of a marrow allograft.

Nevertheless, it was a leap of faith that such rigorous treatment was feasible in humans. As the repopulation of the marrow could take many days, supportive treatment was essential, but platelet transfusions and potent antibiotics lay in the future. Moreover, transplantation immunology was in its infancy. It would be years before the T-cell and B-cell compartments were recognized; human tissue antigens and monoclonal antibodies were unknown; and DNA sequencing and fluorescence activated cell sorting were buried in ignorance (all these advances appeared between 1960 and 1977). In short, we were groping—yet all involved thought that a desperate situation required desperate measures.

Spurred on by Georges Mathé's report of the rescue by marrow allografts of 6 Yugoslavian physicists who were exposed to radiation after a nuclear accident,4 Dameshek decided to treat end-stage leukemia in 3 patients with radiation and marrow rescue. All 3 died soon after receiving the radiation. Almost simultaneously, the first attempt to transplant a renal allograft at the Peter Bent Brigham Hospital, using a variation of the Main and Prehn protocol, ended disastrously (Don Thomas and I extracted marrow from the donor, the patient's brother, while Hartwell Harrison removed his kidney).

Dameshek's ward rounds were memorable, but especially on one unforgettable morning in 1957. Frustrated by the loss of the 3 patients we had subjected to radiation, Dameshek lectured us about the dangers and failures of total body radiation. He said that we need another way to suppress rejection of a marrow allograft. He assigned the task of finding it to me.

Before working on the problem, I read most of the meager literature on cells of the immune system (immunochemistry was in the limelight of immunology during the 1950s). Several investigators found many large unclassified cells in the lymphoid tissues of immunized animals. I looked at these cells with the cytological method for examining bone marrow specimens and saw numerous lymphoblasts, many with mitotic figures, in lymph nodes draining the site of an injection of antigen in rabbits. In a “blind” test, Dameshek could not distinguish these immune cells from lymphoblastic leukemia cells.

My clinical work led me to see if agents with activity in lymphoblastic leukemia, methotrexate and 6-mercaptopurine (6MP), could suppress these immune cells. The experiment was designed to test the drug’s ability to block the immune response of rabbits to a protein antigen. I wrote to George Hitchings at the Burroughs Wellcome Company for a sample of 6MP suitable for injection into rabbits, and to an employee of the Lederle Pharmaceutical Company for a sample of methotrexate. Hitchings promptly sent a package containing 25 mg of 6MP.

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Transplantation: What was the highlight of your scientific career?

RS: The first time I assayed serum from antigen-challenged rabbits remains in my memory, because it was immediately evident that 6MP suppressed the immune response of rabbits to a foreign protein. This Eureka moment changed my life. Seeing the results, another trainee in the division asked, “What happens when you give a second shot of antigen?” So I repeated the experiment, and after a few weeks gave 2 groups of animals (controls and 6MP-treated animals) with a second injection of antigen. Animals that were previously treated with 6MP remained unresponsive to the antigen, whereas untreated animals had a typical anamnestic response. I called the phenomenon “drug-induced immunological tolerance.”5

Luck had a major influence on these experiments. George Hitchings later told me that a variant allele rendered rabbits relatively resistant to methotrexate; they were, however, susceptible to 6MP. If the biology had been the other way around, I would have abandoned the project.

The next question was whether 6MP could prevent allograft rejection. Dick Wilson, a surgical resident at the Brigham, taught me the technique of skin grafting in rabbits. I found that 6MP-treated rabbits retained a skin allograft for a period twice as long as the controls.6 Roy Calne, a surgical resident at the University of Cambridge, England, read my work, and decided to use 6-MP to suppress rejection of renal allografts in dogs. It worked. Roy left Cambridge to continue his experiments at the Brigham. One of his dogs, “Lollypop,” survived over 1 year after bilateral nephrectomy, followed by a renal allograft and 6MP treatment.7 With these results in mind, Hitchings asked Calne and me to try an analog of 6MP, BW5732 (a prodrug that the liver converts to 6MP, later named Imuran). It, too, suppressed the immune response. It was then that we coined a new word, “immunosuppression.” Dameshek and I, being hematologists, began to try 6MP and BW5732 in autoimmune diseases of the blood.8 Our results underpins the development of many other immunosuppressive agents, now used for the treatment of autoimmune diseases.

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Transplantation: Imagine starting your career tomorrow. What would you do differently?

RS: Starting a career in research tomorrow would be vastly different than it was in 1957, when tools and knowledge required for biomedical research were primitive. What I missed most was formal training in fundamental immunology. At one point, in despair because I was having trouble measuring serum antibodies, I went to see Dr. Byron Waksman, an immunologist at the Massachusetts General Hospital. I showed him my results with 6MP and asked him to accept me for more training, even if it meant that I had to quit the 6MP project. He wisely advised me not to quit—“You have interesting results, why abandon the work? Nobody can help you except yourself.”

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Transplantation: How would you advise a resident who is looking for recommendations for combining clinical and research training?

RS: Find the best mentor you can in your field of interest, find a place where you will learn to ask important biological questions. Find the kind of ambiance we had in the late 1950s and throughout the 1960s—investigators from different institutions cooperating in solving a tough problem. Pay attention to statistics.

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Transplantation: What excites you outside of clinical and research interest?

RS: Photography and music.

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REFERENCES

1. Barnes DW, Corp MJ, Loutit JF, et al. Treatment of murine leukaemia with X rays and homologous bone marrow: preliminary communication. Br Med J. 1956; 2: 626–627.
2. Main JM, Prehn RT. Successful skin homografts after the administration of high dosage x radiation and homologous bone marrow. J Natl Cancer Inst. 1955; 15: 1023–1029.
3. Mannick JA, Lochte HL Jr, Ashley CA, et al. A functioning kidney homotransplant in the dog. Surgery. 1959; 46: 821–828.
4. Mathé G. Transfusions et greffes de moelle osseuse homologue chez des humains irradiaés à haute dose accidentellement. Revue français des études cliniques et biologiques. 1958; 4: 3.
5. Schwartz R, Dameshek W. Drug-induced immunological tolerance. Nature. 1959; 183: 1682–1683.
6. Schwartz R, Dameshek W. The effects of 6-mercaptopurine on homograft reactions. J Clin Invest. 1960; 39: 952–958.
7. Calne RY. The rejection of renal homografts. Inhibition in dogs by 6-mercaptopurine. Lancet. 1960; 1: 417–418.
8. Schwartz R, Dameshek W. The treatment of autoimmune hemolytic anemia with 6-mercaptopurine and thioguanine. Blood. 1962; 19: 483–500.
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