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Long-term Kinetics of Intragraft Gene Signatures in Renal Allograft Tolerance Induced by Transient Mixed Chimerism

Matsunami, Masatoshi MD1; Rosales, Ivy A. MD2; Adam, Benjamin A. MD3; Oura, Tetsu MD1; Mengel, Michael MD3; Smith, Rex-Neal MD2; Lee, Hang PhD4; Cosimi, A. Benedict MD1; Colvin, Robert B. MD2; Kawai, Tatsuo MD1

doi: 10.1097/TP.0000000000002911
Original Basic Science–General
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Background. Renal allograft tolerance (TOL) has been successfully induced in nonhuman primates (NHPs) and humans through the induction of transient mixed chimerism. To elucidate the mechanisms of TOL, we compared local immunologic responses in renal allografts with those in T-cell–mediated rejection (TCMR) and chronic antibody–mediated rejection (CAMR) in NHPs.

Methods. Using the NanoString nCounter platform, we retrospectively studied 52 mRNAs in 256 kidney allograft samples taken from NHP kidney recipients of donor BMT. No immunosuppression was given after 1-month post–donor BMT. Recipients who achieved TOL (n = 13) survived for >1840 ± 1724 days with normal kidney function, while recipients with CAMR (n = 13) survived for 899 ± 550 days with compromised graft function, and recipients with TCMR (n = 15) achieved only short-term survival (132 ± 69 days).

Results. The most prominent difference between the groups was FOXP3, which was significantly higher in TOL than in CAMR and TCMR, both early (<1 y, P < 0.01) and late (≥1 y, P < 0.05) after transplant. Other mRNAs related to regulatory T cells (Treg), such as IL10, TGFB, and GATA3, were also high in TOL. In contrast, transcripts of inflammatory cytokines were higher in TCMR, while activated endothelium-associated transcripts were higher in CAMR than in TOL. The receiver operating characteristic analyses revealed that intragraft FOXP3 and CAV1 can reliably distinguish TOL from CAMR.

Conclusions. High FOXP3 and other Treg-related mRNAs together with suppressed inflammatory responses and endothelial activation in renal allografts suggest that intragraft enrichment of Treg is a critical mechanism of renal allograft TOL induced by transient mixed chimerism.

1 Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

2 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

3 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.

4 Department of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Received 24 April 2019. Revision received 25 June 2019.

Accepted 18 July 2019.

M.M. designed and performed the experiments, analyzed data, and wrote the manuscript. T.O. contributed to the experimental design and interpretation of results. B.A.A. performed the NanoString experiments and assisted in the data analysis. M.M. supervised the NanoString experiments. I.A.R. and R.-N.S. helped with the interpretation of the histological analysis. H.L. performed the statistical analysis. A.B.C. edited the manuscript. T.K. and R.B.C. conceived and directed the study and wrote the manuscript.

The authors declare no conflicts of interest.

The present work was supported in part by Grant 5U19AI102405, part of the National Institute of Health Nonhuman Primate Transplantation Tolerance Cooperative Study Group and sponsored by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Canadian Foundation for Innovation. This study was also generously supported by Pablo and Almudena Legorreta Research Fund.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Tatsuo Kawai, MD, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114. (tkawai@mgh.harvard.edu).

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