Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques

Raimon Duran-Struuck, Hugo P. Sondermeijer, Leo Bühler, Paula Alonso-Guallart, Jonah Zitsman, Yojiro Kato, Anette Wu, Alicia N. McMurchy, David Woodland, Adam Griesemer, Mercedes Martinez, Svetlan Boskovic, Tatsuo Kawai, A. Benedict Cosimi, Cheng Shie Wuu, Andrea Slate, Markus Y. Mapara, Sam Baker, Rafal Tokarz, Vivette D'AgatiScott Hammer, Marcus Pereira, W. Ian Lipkin, Thomas Wekerle, Megan K. Levings, Megan Sykes

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Background Infusion of recipient regulatory T (Treg) cells promotes durable mixed hematopoietic chimerism and allograft tolerance in mice receiving allogeneic bone marrow transplant (BMT) with minimal conditioning. We applied this strategy in a Cynomolgus macaque model. Methods CD4+ CD25high Treg cells that were polyclonally expanded in culture were highly suppressive in vitro and maintained high expression of FoxP3. Eight monkeys underwent nonmyeloablative conditioning and major histocompatibility complex mismatched BMT with or without Treg cell infusion. Renal transplantation (from the same BMT donor) was performed 4 months post-BMT without immunosuppression to assess for robust donor-specific tolerance. Results Transient mixed chimerism, without significant T cell chimerism, was achieved in the animals that received BMT without Treg cells (N = 3). In contrast, 2 of 5 recipients of Treg cell+ BMT that were evaluable displayed chimerism in all lineages, including T cells, for up to 335 days post-BMT. Importantly, in the animal that survived long-term, greater than 90% of donor T cells were CD45RA+ CD31+, suggesting they were new thymic emigrants. In this animal, the delayed (to 4 months) donor kidney graft was accepted more than 294 days without immunosuppression, whereas non-Treg cell BMT recipients rejected delayed donor kidneys within 3 to 4 weeks. Early CMV reactivation and treatment was associated with early failure of chimerism, regardless of Treg cell administration. Conclusions Our studies provide proof-of-principle that, in the absence of early CMV reactivation (and BM-toxic antiviral therapy), cotransplantation of host Treg cell can promote prolonged and high levels of multilineage allogeneic chimerism and robust tolerance to the donor.

Original languageEnglish (US)
Pages (from-to)274-283
Number of pages10
JournalTransplantation
Volume101
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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