LASKER~DEBAKEY CLINICAL MEDICAL RESEARCH AWARD ESSAY “It can’t be done” Roy Y Calne In 1950, medical students in the UK were working at the Royal College of Surgeons in early 1960s using independently developed allocated patients for whom we had a special, England, I found that total-body X-ray irradia- blood bypass procedures. personal responsibility and acted as advocate. tion failed to prolong kidney graft survival, but I presented the case of a patient about my age the antileukemia drug 6-mercaptopurine pro- The move to the clinic dying of kidney failure. The senior consultant longed renal allograft survival in dogs. Sir Peter The move of liver transplantation to the clinic told me to make my patient as comfortable as Medawar felt this observation to be worthy of was pioneered in 1963 by Thomas Starzl5, but possible, but, sadly, he would be dead in two intense and prolonged study, and this proved the results of the first pilot study were disas- weeks. I was appalled by this stark prognosis to be the case3, as it led to the introduction of trous, and he decided on a moratorium while and, thinking in terms of gardening, I asked azathioprine, the first effective clinical immu- further experimental work was performed. In whether the patient could receive a kidney nosuppressant. the clinic, only patients desperately ill were graft. The consultant said no, and, when I asked I was fortunate to receive a Harkness referred for consideration of this untried opera- why not, I was told “it can’t be done.” I was per- Fellowship to study at Harvard Medical School tion, and it is not surprising that some of these plexed because it seemed that there were only in Francis Moore’s Department of Surgery, patients were unfit for an anesthetic, let alone a three plumbing junctions required—an artery, where Moore himself was pioneering the tech- liver transplant. The anesthesia and the inten- a vein and the ureter—and surgical techniques nique of liver transplantation in dogs at the sive care after the operation required compli- were available to accomplish these tasks. I had same time that Thomas Starzl was doing similar cated physiological considerations and special no idea of the phenomenon of graft rejection. experiments in Denver. I was therefore exposed training for anesthetists and nurses, so that care I returned to the subject in 1959 after hear- to the formidable technical obstacles to be over- of the patient after the operation by both sur- ing Peter Medawar give a lecture in Oxford come, but my work in Moore’s department was gical and hepatological teams remained at the explaining the immunological nature of graft concentrated on immunosuppression and on same level of vigilance as during the surgical rejection and the exciting experiments that he developing drugs given to me by the Nobel lau- procedure (Fig. 1). Also essential was an in- and his colleagues had done, showing “specific reates George Hitchings and Gertrude Elion, depth understanding of the immunosuppres- immunological tolerance”1. The concept of the who had synthesized 6-mercaptopurine. They sive drugs, none of which was perfect, having developing immune system in the fetus, which suggested that I study a series of compounds, toxic side effects. would accept as a ‘self-product’ any potential and one of them, azathioprine, turned out to be Our own interest in liver transplantation fol- antigen with which it came in contact, raised an a little better than 6-mercaptopurine in terms lowed studies on the immunology of liver trans- important question not yet answered: could an of promoting graft survival4. Azathioprine plants and the unexpected acceptance of liver adult immune system be temporarily returned was used in clinical kidney transplantation grafts that was observed between unrelated pigs to the fetal state while the organ graft was with results that were sometimes encouraging without any immunosuppressive drug treat- inserted, and could the immune system then despite there being many failures. On return- ment. Usually, typical features of rejection were regain its protective role, having accepted the ing to the UK in 1961, I continued with this observed but they resolved spontaneously6, an foreign graft? work and was appointed the Chair of Surgery interesting and previously little studied phe- at Cambridge University in 1965. nomenon that presumably had similarities to Hurdles to transplantation Transplantation of the liver is a formidable the immune reactions that occur after a virus Since 1959, my professional work has been operation, and for those attempting the pro- infection, when the powerful antibody and cell- focused on organ transplantation, and from cedure for the first time, when there was no mediated immunities are switched off after the the beginning it was clear that there were two previous experience, mistakes were made at infection has been defeated. separate series of problems to overcome. The every stage. But gradually a corpus of knowl- Although pigs have been bred over hundreds first was technical and, for the kidney, this was edge developed, and errors were recognized and of years to improve the quality of their meat, solved by Joseph Murray with the successful subsequently avoided. Even in a healthy animal they are in no sense inbred, as are laboratory transplant of a kidney between identical twins2. recipient the orthotropic operation is of great murine strains. The porcine liver graft could also The second was immunological: the biological magnitude, involving removal of the recipient protect other tissues such as kidney and skin rejection of transplanted tissue. In 1959, while liver and thereby totally blocking the return of from the same donor from being rejected. These blood from the inferior vena cava and the intes- observations were supplemented by many stud- Roy Y. Calne is Emeritus Professor of Surgery, tinal portal system to the heart. The physiologi- ies in inbred rats, and it was shown that, between University of Cambridge, Cambridge, UK. cal disturbances were overcome experimentally certain strains, irreversible rejection occurred e-mail: [email protected] by both Starzl and Moore in the late 1950s and and, between others, there was little evidence NATURE MEDICINE VOLUME 18 | NUMBER 10 | OCTOBER 2012 xxiii ESSAY disease and malignancies were the laboratory and first used in clinical organ regarded as too ill to continue transplantation in Cambridge12. Cyclosporin immunosuppression, which improved the one-year kidney graft survival was deliberately stopped. from around 50% to more than 80%. This Some of these patients did not was seized upon by some of those who had reject their liver grafts, others previously been critical of the whole idea of did. The procedure of weaning transplantation, and they became enthusiastic from immunosuppression was supporters and performers of the procedure. investigated extensively in the Prior to the advent of cyclosporine, there Denver/Pittsburgh series9. It were about ten centers seriously performing became apparent that opera- organ transplantation in the world; within a tional tolerance in some cases few years of its introduction there were more was extremely robust, with than 1,000, and the new problem of shortage of patients maintaining good organ donors started to become apparent and function in their grafts for has become increasingly worrisome ever since. many years, whereas in other The introduction of cyclosporine into the cases the tolerance was more clinic improved the results of liver transplan- fragile, and rejection could tation. Another valuable immunosuppressive be precipitated by extraneous drug, FK506, or tacrolimus, was discovered factors, for example, infection. in Japan and brought to the clinic by Starzl Two factors were, in fact, in Pittsburgh. Tacrolimus is a calcineurin known. First, the liver is a inhibitor with a mode of action similar to major source of soluble human cyclosporine. Another powerful immunosup- leukocyte antigen (HLA) class I pressant with a different mode of action and antigen which can have a toxicity profile, rapamycin, was developed in specific immunosuppressive Cambridge13. effect, and approximately half When new immunosuppressive agents of circulating HLA class 1 anti- became available there was a tendency for cli- gen in the blood of recipients of nicians to add them to previous protocols. This liver transplants is produced by often led to severe toxicity, excessive immuno- Figure 1 R.Y. Calne, The Liver Transplant Patient and The Tribute the donor organ. Second, there suppression, infection and a deterioration of to the Compassion and Skill of the Intensive Care Nurse. Oil on is well-recorded trafficking of clinical results. Our observation of liver toler- canvas, 4 × 3 ft. Commissioned by Goran Klintmalm of the Liver cells between the liver graft ance in the pig with the spontaneous resolution Institute in Dallas. and recipient, particularly of of immunological rejection suggested to us that passenger leukocytes and espe- any approach toward achieving the goal of of rejection. Some rat liver transplants behaved cially Kupffer cells, and it has been suggested immunological tolerance would require active in a manner similar to those in pigs, with rejec- that these play an important part in the relative engagement of the immune system of the recip- tion and then spontaneous recovery. Reports of lack of rejection of liver allografts, producing ient with donor tissue. Excessive immunosup- these experiments provoked the Lancet to write ‘microchimerism’, which may have a specific pression might prevent this engagement and a leading article entitled “Strange English Pigs”7. immunosuppressive effect10. prevent tolerance. We hypothesized that a win- However, the phenomenon was not limited to Despite the failure to provide a complete dow of opportunity for immunological engage- the origin of the pigs and was repeated in other picture to explain the phenomenon, the obser- ment, or ‘WOFIE’, might be an essential step in laboratories8.