New approaches to immunosuppression in renal transplantation.

Although the incidence of 1 year kidney graft survival has been on a plateau for the past 7 or 8 years, the likelihood of recipient survival has increased. These observations reflect the limits of our current nonspecific immunosuppressive techniques and the acquisition of knowledge about when to discontinue their use and allow rejection of the kidney rather than death from sepsis. Yet, there are many leads from the laboratory which, when applied clinically in the next few years, should allow safe kidney transplantation to become a routine clinical event. Among these are safer, more effective antilymphocyte preparations; precise indications for splenectomy; accurate identification of presensitized states in potential recipients; methods of reducing the immunogenicity of grafts by removing donor passenger leukocytes or flushing the kidney with substances that alter surface antigens; and possibly new classes of chemical immunosuppressive drugs. In addition, it is likely that techniques will evolve for selective suppression of the immune response to donor antigens. This will be achieved by using cytotoxic agents coupled to donor antigen to destroy specific antigen recognition lymphocytes. Other forms of noncytotoxic donor antigen and antibody with or without ALS will be used to manipulate the recipient's immune response prior to and after transplantation. These manipulations will leave intact most of the potential for immune response to antigens other than those introduced with the graft. Together, these manipulations and their effect in experimental animals have been called immunologic enhancement. Intentional enhancement in man by means of antigen treatment or passive immunization has just barely begun. Clinical trials will be difficult and, initially at least, they will be confined to only a few transplantation centers. Yet, the "antigen pretreatment" of natural pregnancy, blood transfusion, prior unsuccessful organ transplantation, and bacterial infection have at times inadvertently conditioned a potential host so as to allow enhancement of a subsequent graft. It is likely that much can be done with current clinical assays of cellular and humoral immunity to detect those patients who are already conditioned to enhance a subsequent graft.