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-β⁺ 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 transvivo assays. In contrast, allograft acceptors with TGF-β1⁺ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8 ⁺ 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.