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


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.

SUBMITTER: Burwitz BJ 

PROVIDER: S-EPMC5681693 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Burwitz Benjamin J BJ   Wu Helen L HL   Abdulhaqq Shaheed S   Shriver-Munsch Christine C   Swanson Tonya T   Legasse Alfred W AW   Hammond Katherine B KB   Junell Stephanie L SL   Reed Jason S JS   Bimber Benjamin N BN   Greene Justin M JM   Webb Gabriela M GM   Northrup Mina M   Laub Wolfram W   Kievit Paul P   MacAllister Rhonda R   Axthelm Michael K MK   Ducore Rebecca R   Lewis Anne A   Colgin Lois M A LMA   Hobbs Theodore T   Martin Lauren D LD   Ferguson Betsy B   Thomas Charles R CR   Panoskaltsis-Mortari Angela A   Meyers Gabrielle G   Stanton Jeffrey J JJ   Maziarz Richard T RT   Sacha Jonah B JB  

Nature communications 20171110 1


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 di  ...[more]

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