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

Benjamin J. Burwitz, Helen L. Wu, Shaheed Abdulhaqq, Christine Shriver-Munsch, Tonya Swanson, Alfred W. Legasse, Katherine B. Hammond, Stephanie L. Junell, Jason S. Reed, Benjamin N. Bimber, Justin M. Greene, Gabriela M. Webb, Mina Northrup, Wolfram Laub, Paul Kievit, Rhonda MacAllister, Michael K. Axthelm, Rebecca Ducore, Anne Lewis, Lois M. A. Colgin, Theodore Hobbs, Lauren D. Martin, Betsy Ferguson, Charles R. Thomas, Angela Panoskaltsis-Mortari, Gabrielle Meyers, Jeffrey J. Stanton, Richard T. Maziarz and Jonah B. Sacha ()
Additional contact information
Benjamin J. Burwitz: Oregon Health & Science University, 505 NW 185th Avenue
Helen L. Wu: Oregon Health & Science University, 505 NW 185th Avenue
Shaheed Abdulhaqq: Oregon Health & Science University, 505 NW 185th Avenue
Christine Shriver-Munsch: Oregon Health & Science University, 505 NW 185th Avenue
Tonya Swanson: Oregon Health & Science University, 505 NW 185th Avenue
Alfred W. Legasse: Oregon Health & Science University, 505 NW 185th Avenue
Katherine B. Hammond: Oregon Health & Science University, 505 NW 185th Avenue
Stephanie L. Junell: Oregon Health & Science University
Jason S. Reed: Oregon Health & Science University, 505 NW 185th Avenue
Benjamin N. Bimber: Oregon Health & Science University, 505 NW 185th Avenue
Justin M. Greene: Oregon Health & Science University, 505 NW 185th Avenue
Gabriela M. Webb: Oregon Health & Science University, 505 NW 185th Avenue
Mina Northrup: Oregon Health & Science University, 505 NW 185th Avenue
Wolfram Laub: Oregon Health & Science University
Paul Kievit: Oregon Health & Science University, 505 NW 185th Avenue
Rhonda MacAllister: Oregon Health & Science University, 505 NW 185th Avenue
Michael K. Axthelm: Oregon Health & Science University, 505 NW 185th Avenue
Rebecca Ducore: Oregon Health & Science University, 505 NW 185th Avenue
Anne Lewis: Oregon Health & Science University, 505 NW 185th Avenue
Lois M. A. Colgin: Oregon Health & Science University, 505 NW 185th Avenue
Theodore Hobbs: Oregon Health & Science University, 505 NW 185th Avenue
Lauren D. Martin: Oregon Health & Science University, 505 NW 185th Avenue
Betsy Ferguson: Oregon Health & Science University, 505 NW 185th Avenue
Charles R. Thomas: Oregon Health & Science University
Angela Panoskaltsis-Mortari: Department of Pediatrics, University of Minnesota
Gabrielle Meyers: Knight Cancer Institute, Oregon Health & Science University
Jeffrey J. Stanton: Oregon Health & Science University, 505 NW 185th Avenue
Richard T. Maziarz: Knight Cancer Institute, Oregon Health & Science University
Jonah B. Sacha: Oregon Health & Science University, 505 NW 185th Avenue

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01631-z

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