"Prope" tolerance: induction, lymphocyte depletion with minimal maintenance.

In the 50 years since successful clinical kidney transplantation between identical twins by Murray and his colleagues in Boston, organ transplantation has become established world-wide with ever-improving results, conferring immense benefit to hundreds of thousands of patients. For all organ transplants, the general principles of the surgical procedure and organ preservation have been accepted. Immunosuppression has, however, been more difficult to handle. The demonstration that organ rejection is an immune process by Medawar and colleagues in the 1940s raised a specter of caution that, to prevent rejection of a graft, damage to the host’s immune system could lead to devastating and uncontrollable infection or malignancy. Nevertheless, it was shown that total destruction of the recipient’s immune system by x-irradiation followed by infusion of bone marrow from a donor could restore immune capacity and in many cases give relief to and even cure life-threatening hematologic diseases. However, with few exceptions, the requirement was a close match of the major histocompatibility markers of donor and recipient, especially good results being obtained in bone-marrow transplantation between human leukocyte antigen-identical siblings. Successful bone-marrow transplantation leads to permanent tolerance that extends to other tissues from the same donor, for instance, kidney grafts. The discovery of naturally acquired immunologic tolerance and experimental methods of producing tolerance by Billingham, Brent, and Medawar, although having no obvious direct clinical application, raised the hopes of clinicians that perhaps there might be a means of returning the recipient to a state of temporary immunologic plasticity similar to that occurring in fetal development but with an acceptance of the graft coinciding with the induced plasticity. After the introduction of drug treatment to achieve immunosuppression, initially with azathioprine and corticosteroids in the 1960s, there have been a succession of new immunosuppressive agents investigated experimentally, and a number have been introduced into the clinic. Polyclonal and monoclonal antibodies reacting against human lymphocytes have added to the therapeutic armamentarium of clinicians. There has been an unfortunate tendency to add more and more potent immunosuppressive agents to the patient’s therapy, with concomitant over-immunosuppression occurring frequently and the side effects of the individual drugs causing morbidity and mortality, particularly the nephrotoxic effects of the calcineurin inhibitors. Bone-marrow or stem-cell transplantation has also advanced with new regimens of nonablative transplantation with mixed chimerism, initially planned to retain the graft-against-leukemia effect but also used in a very important series of experiments in patients subsequently given kidney transplants, where tolerance has occurred despite the disappearance of the donor chimeric state in the blood (1). In addition to being expensive, the conventional drug regimen can cause great hardship to patients, and noncompliance is common. Some patients with liver transplants stopped taking their drugs and performed a clinical experiment of demonstrating immunologic tolerance, surviving many years with good liver function despite the absence of any maintenance immunosuppression. Other patients were not so lucky, and this weaning of maintenance immunosuppression is far more likely to be successful with liver transplants than with kidney transplants, which is consistent with experimental demonstration of liver tolerance without any drugs after orthotopic liver transplantation in pigs and rodents. Although a fully understood mechanism of tolerance is desirable, from the patient’s point of view, “operational immunologic tolerance” would be satisfactory, but because of the enormous variation of major histocompatibility complex polymorphism, red cell blood groups, and variability of recipient immune potential, it is unlikely that an across the board tolerance protocol will be rapidly achieved. Nevertheless, in some cases, as in the liver patients mentioned above, this has occurred. It is likely that the next phase of immunosuppression will be the use of a powerful induction agent followed by minimal nonsteroidal maintenance immunosuppression, eventually changing calcineurin inhibitor to a non-nephrotoxic maintenance regimen in most patients, and perhaps weaning a minority of patients off maintenance immunosuppression altogether. This aim of minimal nonsteroidal immunosuppression has been called prope or almost tolerance (2). From the patient’s point of view, minimal immunosuppression without obvious side effects is an attractive proposal compared with conventional immunosuppression, and also, the costs of maintenance immunosuppression should be far less. Two agents in particular have been used for the induction, Campath 1H monoclonal antibody, which is an extremely powerful lympholytic agent, and polyclonal Thymoglobulin, also a lympholytic agent but without producing in acceptable dosage the degree of lymphopenia that occurs with Campath. The 5-year follow-up of the first patients treated with Campath induction and maintenance low-dose cyclosporine have been satisfactory (3). Many patients who have remained on monotherapy without steroids have done well, but there have also been episodes of late rejection, and sometimes rejection occurs even when there are no lymphocytes in that circulating blood, possibly attributed to homeostatic proliferation of memory cells in the relatively lymphocyte-depleted environment (4). Department of Surgery, University of Cambridge, Cambridge, UK. Address correspondence to: Sir Roy Calne, Department of Surgery, Douglas House Annex, 18 Trumpington Rd., Cambridge CB2 2AH, UK. E-mail: cpr1000@cam.ac. uk. Copyright © 2005 by Lippincott Williams & Wilkins ISSN 0041-1337/05/8001-6 DOI: 10.1097/01.TP. 0000164351.72220. 1A