CHRONICALLY REJECTED RAT-KIDNEY ALLOGRAFTS INDUCE DONOR-SPECIFIC TOLERANCE

Previous studies on pathophysiological mechanisms of chronic graft rej ection demonstrated the impact of both alloresponsiveness and nonspeci fic immunological events on the process. To study the role of alloanti gen-specific factors further, we hypothesized an acceleration of chron ic graft rejection after presensitization, Chronically rejected renal allografts in the established Fischer 344 --> Lewis rat model were rep laced sequentially by native allografts of donor origin. Grafting of s econd allografts was performed 2, 4, 8, and 12 weeks after the origina l transplantation and followed long term. Second allografts demonstrat ed significantly ameliorated functional and structural alterations wit h few cellular infiltrates. These changes were independent from the ti me interval between first and second engraftment (2-12 weeks); immunos uppressive treatment after the second engraftment was not influential, The nonresponsiveness was not restricted to the second kidney allogra fts, as heart allografts of donor origin in these recipients also func tioned indefinitely, whereas third-party grafts (Lewis x Brown Norway F-1) and Fischer 344 heart grafts in untreated Lewis control rats were acutely rejected. Thus, donor-specific and tissue-nonspecific graft a cceptance is achieved by second engraftment of donor-specific allograf ts in a model of chronic graft rejection. Those observations demonstra te the synergistic effects of alloresponsiveness and of the injured gr aft itself for the development of chronic graft failure.