Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques.
- Duran-Struuck R Columbia University Medical Center, New York, NY, United States.
- Sondermeijer HP Columbia University Medical Center, New York, NY, United States.
- Bühler L Geneva University Hospital, Geneva, Switzerland.
- Alonso-Guallart P Columbia University Medical Center, New York, NY, United States.
- Zitsman J Columbia University Medical Center, New York, NY, United States.
- Kato Y Columbia University Medical Center, New York, NY, United States.
- Wu A Columbia University Medical Center, New York, NY, United States.
- McMurchy AN University of British Columbia, Vancouver, British Columbia, Canada.
- Woodland D Columbia University Medical Center, New York, NY, United States.
- Griesemer A Columbia University Medical Center, New York, NY, United States.
- Martinez M Columbia University Medical Center, New York, NY, United States.
- Boskovic S Massachusetts General Hospital, Boston. MA, United States.
- Kawai T Massachusetts General Hospital, Boston. MA, United States.
- Cosimi AB Massachusetts General Hospital, Boston. MA, United States.
- Yang YG Columbia University Medical Center, New York, NY, United States.
- Hu Z Columbia University Medical Center, New York, NY, United States.
- Wuu CS Columbia University Medical Center, New York, NY, United States.
- Slate A Columbia University Medical Center, New York, NY, United States.
- Mapara M Columbia University Medical Center, New York, NY, United States.
- Baker S Columbia University Medical Center, New York, NY, United States.
- Tokarz R Columbia University Medical Center, New York, NY, United States.
- D'Agati V Columbia University Medical Center, New York, NY, United States.
- Hammer S Columbia University Medical Center, New York, NY, United States.
- Pereira M Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna, Austria.
- Lipkin WI University of British Columbia, Vancouver, British Columbia, Canada.
- Wekerle T Columbia University Medical Center, New York, NY, United States.
- Levings M
- Sykes M
- 2016-11-16
Published in:
- Transplantation. - 2017
Allografts
Animals
Antiviral Agents
Biomarkers
Bone Marrow Transplantation
Cell Proliferation
Cells, Cultured
Cytomegalovirus Infections
Graft Rejection
Graft Survival
Histocompatibility
Histocompatibility Antigens
Kidney Transplantation
Macaca fascicularis
Male
Models, Animal
T-Lymphocytes, Regulatory
Time Factors
Transplantation Chimera
Transplantation Conditioning
Transplantation Tolerance
English
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 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.
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.
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 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.
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1097/TP.0000000000001559
- PMID 27846155
- Persistent URL
- https://sonar.ch/global/documents/232613
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