Fifty years in the vineyard of transplantation: looking back.

The past 5 decades have documented remarkable advances in basic knowledge and clinical expertise in transplantation. The first 12 years of this half century of my participation in the enterprise were consumed with the isolation, chemical characterization, and application of histocompatibility antigens purified from mouse, guinea pig, and human tissues, demonstrating that their specificity was based on unique amino acid sequences in protein structures. Initial unsuccessful attempts to use native molecules to induce tolerance in rat renal or heart transplantation models were followed by limited success when they were administered with a brief perioperative course of cyclosporine (CsA). Production of allochimeric constructs of class I major histocompatibility complex molecules bearing donor-type amino acid substitutions into the host-type C-terminal portion of the α1 helix yielded tolerogens whose activity was not dependent on conditioning with CsA or total lymphoid irradiation (TLI). The allochimeric molecules serve as altered peptide ligands that induce an aberrant T-cell signal 1 response producing transplantation tolerance. The potent activity of CsA in this experimental model was extended to clinical settings. Pharmacologic tools were employed to explore intra- and interindividual variations in drug exposure leading to the development of a better drug formulation. However, the intrinsic nephrotoxicity of CsA necessitated marked 80% reductions in de novo drug exposure as were achieved by exploiting the synergistic pharmacodynamic and pharmacokinetic interactions of CsA with sirolimus. The final decade in this 50-year experience includes editorship of this journal with marked changes in its direction. These experiences have afforded insights into future avenues for preclinical exploration and therapeutic drug development.