The immunosuppressive therapy of acute rejection in liver transplantation : new strategies and their pathophysiological bases

Although most of the organ transplantation attempts performed during the first falh of this century have been technical successes, all of them resulted in functional failure, due to a phenomenon described by Peter Medawar in 1944 as the “homograft response”. This reaction of the host was characterized as constituted by a specific cellular response (first set) directed towards the allograft, leading to its destruction, and inducing a memory process, leading itself to accelerated rejection (second set) of a second transplant of the same donor strain (311). In 1954, Mitchison discovered that the transfer of antigen-sensitized lymphocytes from an immunized to a naïve individual may result in second-set transplant-set transplant rejection, indicating the cellular nature of the allograft immune response (317).
The deliberate depression of immunological reactivity became theoretically feasible for human transplantation when total body irradiation and adrenal cortical steroids were shown to be immunosuppressive in animals (38,115). The next great step was the introduction of 6-mercaptopurine and its imidazole derivative azathioprine, shown to inhibit rejection of skin and renal allograft in several experimental models (57,58,312). The down of the modern era of transplantation came with the realization that azathioprine and prednisolone had at least additive, and possibly synergistic, effects (494). The most important new progress between 1962 and 1978 was the adjuvant use of antilymphocyte globulin, combined with azathioprine (or cyclophosphamide) and steroids (492). Ultimately, it became possible to produce a more potent and specific antithymocyte antibody (Ab), using the hybridoma technique discovered by Kohler and Milstein (93,255).
The human kidney transplant served as a prototype for secondary application of the current immunosuppressive protocol to the extrarenal organs (477). In contrast, the early steps of liver replacement took place in the field of surgical technique. The implantation of auxiliary whole livers in dogs was described in 1955 by Welch (562), and, within 5 years, attempts at total host hepatectomy and orthotopic canine liver transplantation were successful at both Harvard and North-western University (319,487); technical problems and the features or rejection in untreated animals were delineated (180, 488, 493). Under immuinosuppression with azathioprine or anti-lymphocyte serum, long-term survival was achieved after liver replacement in a number of mongrel dogs (492). In pigs, it was soon found that rejection of hepatic allografts was relatively mild in comparison with that in dogs and that many orthotopic porcine grafts supported life for a long time without immunosuppression (64).
The first human orthotopic liver transplantation (OLT° was performed 30 years ago, in 1963, by T.E. Starzl, and the basic surgical principles of this procedure were almost worked out by the end of the sixties (484,486,490). Twenty years after this first attempt, in 1983, the National Institute of Health consensus development conference accepted liver transplantation as a “therapeutic modality for end-stage liver disease that deserves broader application” (329). This marked the beginning of a rapid expansion on liver transplantations activity, and there has been an exponential rise in the number of grafts performed in Europe as well as in the USA (36, 239). Beside refinements of surgical technique and postoperative care, development of the highly effective immunosuppressive agent cyclosporine A (CyA), introduced into clinical transplantation in 1979 (60), has dramatically reduced morbidity and mortality: one-year survival figures of 80 or more in non-malignant cases have been reported by a number of units, and it seems likely that the overall figures will reach this level in the near future (239,288,343,413,481,482).
Between 1982 and 1990, a total of 9761 human liver allo-transplantation had been performed in the United States (138), whereas, according to the European Liver Transplant Registry, 14713 cases were carried out in Europe between May 1968 and December 1993; however, despite this vast clinical experience, acute rejection (AR) still constitutes the most common cause of post-transplant hepatic dysfunction, beside other conditions including ischemic damage, biliary obstruction, vascular thrombosis, viral infection, and drug-induced hepatic injury (25,249). As shown in Table 2, the incidences of rejection in liver allografting have remained high in a majority of centers, at 57 – 100 % for acute, and up to 29% in some groups for chronic rejection (35,51,96,151,181,249,249,309,323,334,344,418,416,471,512,531,541). Acute immunological injury of the liver grafts leads to the need to rein-force immunosuppression, with a consequent risk of increased morbidity and prolongation of hospital stay; graft loss from chronic rejection (CR) leads to retransplantation, with high mortality rates (388,447). According, prevention and therapy of AR of the hepatic allograft still represents major clinical challenges, and immunosuppression may be regarded today as one of the “Achilles’ heels” of liver transplantation.
Since 1985, we have been involved in the development of some innovative immunosuppressive strategies in the field of organ transplantation in general, and in liver transplantation in particular, which will be illustrated in this work. These clinical and experimental approaches of immunoprophylaxis and therapy will introduce the discussion of some pathophysiological mechanisms of AR and of induced graft acceptance in liver transplantation