The Knife’s Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques

H. B. Zheng, B. Watkins, V. Tkachev, S. Yu, D. Tran, S. Furlan, K. Zeleski, K. Singh, K. Hamby, C. Hotchkiss, J. Lane, S. Gumber, A. B. Adams, L. Cendales, A. D. Kirk, A. Kaur, B. R. Blazar, C. P. Larsen, L. S. Kean

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.

Original languageEnglish (US)
Pages (from-to)657-670
Number of pages14
JournalAmerican Journal of Transplantation
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Funding Information:
This work was funded by NIH NIAID 5U19-AI051731 (L.S.K., C.P.L., A.B.A., A.D.K.), NIH NHLBI 5 R01 HL095791 (L.S.K.) and P01 AI056299 (B.R.B.). We gratefully acknowledge the work of Dr. Cecelia Penedo and Ms. Thea Ward of the California National Primate Research Center as well as Dr. Roger Wiseman and Dr. David O?Connor, who performed microsatellite-based MHC typing and chimerism analysis for this study. We thank the veterinary staff of both the Yerkes National Primate Research Center and the Washington National Primate Research Center for their expert veterinary assistance with these studies.

Publisher Copyright:
© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • animal models: nonhuman primate
  • bone marrow/hematopoietic stem cell transplantation
  • tolerance: chimerism
  • translational research/science

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