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Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-1⁺CD4⁺ T Regulatory Cell Infiltrates¹

Jose R. Torrealba^2,*, Masaaki Katayama^2,, John H. Fechner, Jr., Ewa Jankowska-Gan, Satoshi Kusaka, Qingyong Xu, Jacqueline M. Schultz, Terry D. Oberley^*, Huaizhong Hu, Majed M. Hamawy, Margreet Jonker, Jacqueline Wubben, Gaby Doxiadis, Ronald Bontrop, William J. Burlingham^3, and Stuart J. Knechtle

^* Department of Pathology, University of Wisconsin and Veterans Affairs Hospital, and Department of Surgery, University of Wisconsin, Madison, WI 53792; and Biomedical Primate Research Center, Rijswijk, The Netherlands

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-1⁺ 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-1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-1. Peripheral leukocytes from rejecting monkeys lacking TGF-1⁺ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-1⁺ 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-1 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-1. 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.

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