Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates

Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β1 + interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1 + allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-β1 + infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens ( p + and CD4 + interstitial T cell infiltrates, but only the CD4 + subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4 + T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.