INTERFERON-GAMMA-TREATED RENAL TUBULAR EPITHELIAL-CELLS INDUCE ALLOSPECIFIC TOLERANCE

Following organ transplantation, tissue parenchymal cells commonly exp ress major hiocompatibility complex (MHC) class II molecules as a resu lt of local cytokine release, and thus acquire the capacity to present donor MHC alloantigens to alloreactive CD4(+) T cells. The consequenc es of such a presentation are likely to be relevant in the induction o f tolerance to the transplanted tissues, and this has been reported in animal models of transplantation and in humans. In this study, the co nsequences of antigen presentation by interferon-gamma (IFN-gamma)-tre ated human renal tubular epithelial cells (RTEC) to resting and activa ted CD4(+) T cells were investigated. Allogeneic RTEC were unable to s timulate proliferation by peripheral blood CD45 RA(+) or RO+ CD4(+) T cells from three HLA-mismatched responders. The response to RTEC was p artially reconstituted by the addition of murine L cell transfectants expressing human B7.1 (DAP.3-B7), suggesting that the failure of RTEC to stimulate a primary alloresponse was due, at least in part, to a la ck of costimulation. T cell clones dependent on B7-mediated co-stimula tion also did not respond to peptide presented by RTEC. Most important ly, this lack of reactivity was accompanied by the induction of nonres ponsiveness. Incubation with allogeneic, DR-expressing RTEC induced al lospe cific hyporesponsiveness in both CD45RA(+) and RO+ T cells. Simi larly, overnight incubation with antigen-pulsed RTEC induced nonrespon siveness in the B7-dependent T cell clones. These results suggest that MHC class II expression on RTEC may contribute to the induction of an allospecific nonresponsiveness following organ transplantation.