EVIDENCE FOR CLONAL ANERGY AS A MECHANISM RESPONSIBLE FOR THE MAINTENANCE OF TRANSPLANTATION TOLERANCE

The main stimulus triggering early acute allograft rejection is known to be delivered by the allogeneic ''passenger'' leukocytes present wit hin the grafts. Once these cells have been replaced by cells of recipi ent origin, subsequent rejection episodes are generally less frequent and less acutely destructive. How this replacement affects the cell po pulations responsible for allograft rejection is not known. Here we re port that rat alloreactive non-cytotoxic AS (RT1l) anti-August (RT1c) CD4+ T cells, that were shown to be specific for RT1.B(c+) August sple en stimulators, were able to cause acute rejection of normal August ki dney allografts transplanted into sublethally irradiated AS recipients . These cells, however, failed to reject passenger cell-depleted (PCD) August kidneys, despite the substantial expression of RT1.B(c+) produ cts on the graft tubular epithelium. In experiments in vitro, August k idney tubular epithelial cells expressing RT1.B(c+) antigens were foun d to be unable to stimulate the alloreactive T cells to proliferate. M oreover, preincubation with class II-positive August kidney epithelial cells specifically abrogated the alloreactivity of the T cells. Addin g recombinant interleukin-2, however, restored the response to alloant igens. These results are consistent with the hypothesis that T cell po pulations capable of mediating early acute allograft rejection are dif ferent from those mediating late rejection, when donor passenger leuko cytes are no longer present. They also suggest clonal anergy as one of the mechanisms responsible for maintaining long-term transplantation tolerance.