The mode of action of immunosuppressive drugs

The immunosuppression first introduced in the 1950s acted indiscriminately, blocking or damaging all the cells that happened to be in mytosis. The toxic side effects were usually so severe that the overall results were not considered satisfactory. The major drawback to the commonly used combination of steroids and cytotoxic drugs is the high risk of overwhelming infections. The next step was the development of lymphocytotoxic drugs or procedures which were restricted to the elimination of the immunocompetent cells. This was achieved by the use of total lymphoid irradiation, thoracic duct cannulation, antilymphocyte globulin, L-asparaginase and steroids. Steroids not only intervene at many points of the immune response, but they also possess a remarkable anti-inflammatory potency. The current or third stage is that of immunopharmacology, which is characterized by selective immunoregulation using compounds or methods that specifically modulate defined subpopulations of immunocompetent cells. Ciclosporin is the first drug that fulfilled these requirements to some extent and that has proved of permanent clinical value. The new technology of monoclonals has allowed the production of highly specific antibodies directed toward lymphocyte subsets. The modulation of lymphokines is another potential approach for both immunosuppression and immunostimulation. The final phase of immunosuppression will be the induction of antigen-specific depression of allograft reactivity. Classical transplantation tolerance has been induced in a developing immune system, but it is virtually impossible to achieve in a fully developed immune system.