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Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates

Thaiss, Cornelius C.1,2; Oura, Tetsu, MD, PhD1; Sasaki, Hajime, MD, PhD1; Dehnadi, Abbas, DVM1; Matsunami, Masatoshi, MD1; Rosales, Ivy A., MD3; Cosimi, A. Benedict, MD1; Kawai, Tatsuo, MD, PhD1

doi: 10.1097/TP.0000000000002470
Original Basic Science—General
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Background. Although induction of durable mixed chimerism is required for murine skin allograft tolerance (TOL), renal allograft TOL has been achieved after induction of only transient mixed chimerism in nonhuman primates (NHPs) and humans. To better define the level/duration of chimerism required for stable renal allograft TOL, we retrospectively analyzed these parameters and compared them with transplant outcomes in NHP combined kidney and bone marrow transplant recipients.

Methods. Peripheral blood levels and duration of myeloid or lymphoid chimerism were retrospectively analyzed in 34 NHP combined kidney and bone marrow transplantation recipients which were divided into 3 groups: TOL, n = 10; chronic antibody-mediated rejection (CAMR), n = 12; and T cell-mediated rejection (TCMR), n = 12.

Results. All 4 of the recipients that failed to develop any chimerism lost their allografts due to TCMR after discontinuation of immunosuppression (56 ± 3 d). Among 30 recipients who successfully developed multilineage chimerism, 10 achieved long-term immunosuppression-free survival without rejection (1258 ± 388 d), 12 eventually developed CAMR (932 ± 155 d), and 8 developed TCMR (82 ± 10 d). The maximum level but not duration of lymphoid chimerism was significantly higher in TOL recipients compared with both CAMR (P = 0.0159) and TCMR (P = 0.0074). On the other hand, the maximum myeloid chimerism was significantly higher in TOL than in TCMR (P = 0.0469), but not in CAMR. Receiver operating characteristic analyses revealed that lymphoid chimerism levels of 3.1% or greater could reliably predict long-term immunosuppression-free renal allograft survival (P < 0.0001).

Conclusions. This retrospective study confirmed that induction of chimerism is essential for long-term immunosuppression-free survival, which best correlates with lymphoid chimerism levels higher than 3.1%.

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

2 Dr. von Hauner Children’s Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, Germany.

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

Received 21 May 2018. Revision received 7 September 2018.

Accepted 25 September 2018.

This work was supported by NIH grant U19 AI102405-01.

The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. This manuscript was also not prepared or funded by any commercial organization.

C.C.T. participated in the data analysis and wrote the article. T.O. performed the research, data analysis, and writing the article. H.S. performed the research. A.D. performed the research. M.M. performed the research. I.R. performed the research. A.B.C. wrote the article. T.K. designed the study, performed the research, data analysis, and wrote the article.

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, PhD, 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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