title: Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques.
abstract: 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.
  
  
  
  CD4 CD25 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Raimon
authors.initials: R
authors.lastname: Duran-Struuck
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Hugo P
authors.initials: HP
authors.lastname: Sondermeijer
authors.affiliation: Geneva University Hospital, Geneva, Switzerland.
authors.forename: Leo
authors.initials: L
authors.lastname: Bühler
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Alonso-Guallart
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Jonah
authors.initials: J
authors.lastname: Zitsman
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Yojiro
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Anette
authors.initials: A
authors.lastname: Wu
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Alicia N
authors.initials: AN
authors.lastname: McMurchy
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: David
authors.initials: D
authors.lastname: Woodland
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Griesemer
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Massachusetts General Hospital, Boston. MA, United States.
authors.forename: Svetlan
authors.initials: S
authors.lastname: Boskovic
authors.affiliation: Massachusetts General Hospital, Boston. MA, United States.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Massachusetts General Hospital, Boston. MA, United States.
authors.forename: A Benedict
authors.initials: AB
authors.lastname: Cosimi
authors.forename: Yong-Guang
authors.initials: YG
authors.lastname: Yang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Cheng-Shie
authors.initials: CS
authors.lastname: Wuu
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Slate
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Mapara
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Sam
authors.initials: S
authors.lastname: Baker
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Rafal
authors.initials: R
authors.lastname: Tokarz
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Hammer
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Marcus
authors.initials: M
authors.lastname: Pereira
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
authors.affiliation: University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: Levings
authors.affiliation: Columbia University Medical Center, New York, NY, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D064591:Allografts; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003586:Cytomegalovirus Infections / Q000188:drug therapy / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival; D006648:Histocompatibility; D006649:Histocompatibility Antigens / Q000276:immunology* / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D023421:Models, Animal; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D023001:Transplantation Tolerance
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D006649:Histocompatibility Antigens