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Nat Commun. 2017 Nov 10;8(1):1418. doi: 10.1038/s41467-017-01631-z.

Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.

Author information

1
Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR, 97006, USA.
2
Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR, 97006, USA.
3
Division of Medical Physics, Department of Radiation Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
4
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN, 55454, USA.
5
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
6
Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR, 97006, USA. sacha@ohsu.edu.
7
Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR, 97006, USA. sacha@ohsu.edu.

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.-tumor immunity are hampered by the lack of a physiologically relevant, preclinical model of allogeneic HSCT. Here we show a spectrum of diverse clinical HSCT outcomes including primary and secondary graft failure, lethal GvHD, and stable, disease-free full donor engraftment using reduced intensity conditioning and mobilized peripheral blood HSCT in unrelated, fully MHC-matched Mauritian-origin cynomolgus macaques. Anti-GvHD prophylaxis of tacrolimus, post-transplant cyclophosphamide, and CD28 blockade induces multi-lineage, full donor chimerism and recipient-specific tolerance while maintaining pathogen-specific immunity. These results establish a new preclinical allogeneic HSCT model for evaluation of GvHD prophylaxis and next-generation HSCT-mediated therapies for solid organ tolerance, cure of non-malignant hematological disease, and HIV reservoir clearance.

PMID:
29127275
PMCID:
PMC5681693
DOI:
10.1038/s41467-017-01631-z
[Indexed for MEDLINE]
Free PMC Article

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