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

Jose R. Torrealba, Masaaki Katayama, John H. Fechner, 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, Stuart J. Knechtle

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62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5753-5764
Number of pages12
JournalJournal of Immunology
Volume172
Issue number9
DOIs
StatePublished - May 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Torrealba, J. R., Katayama, M., Fechner, J. H., Jankowska-Gan, E., Kusaka, S., Xu, Q., Schultz, J. M., Oberley, T. D., Hu, H., Hamawy, M. M., Jonker, M., Wubben, J., Doxiadis, G., Bontrop, R., Burlingham, W. J., & Knechtle, S. J. (2004). Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates. Journal of Immunology, 172(9), 5753-5764. https://doi.org/10.4049/jimmunol.172.9.5753