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 within the grafts. Once these cells have been replaced by cells of recipient origin, subsequent rejection episodes are generally less frequent and less acutely destructive. How this replacement affects the cell populations responsible for allograft rejection is not known. Here we report that rat alloreactive non-cytotoxic AS (RT1I) anti-August (RT1c) CD4+ T cells, that were shown to be specific for RT1.Bc+ August spleen stimulators, were able to cause acute rejection of normal August kidney 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.Bc+ products on the graft tubular epithelium. In experiments in vitro, August kidney tubular epithelial cells expressing RT1.Bc+ antigens were found to be unable to stimulate the alloreactive T cells to proliferate. Moreover, preincubation with class II-positive August kidney epithelial cells specifically abrogated the alloreactivity of the T cells. Adding recombinant interleukin-2, however, restored the response to alloantigens. These results are consistent with the hypothesis that T cell populations capable of mediating early acute allograft rejection are different from those mediating late rejection, when donor passenger leukocytes are no longer present. They also suggest clonal anergy as one of the mechanisms responsible for maintaining long-term transplantation tolerance.