TY - JOUR
T1 - Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes
AU - Burwitz, Benjamin J.
AU - Wu, Helen L.
AU - Abdulhaqq, Shaheed
AU - Shriver-Munsch, Christine
AU - Swanson, Tonya
AU - Legasse, Alfred W.
AU - Hammond, Katherine B.
AU - Junell, Stephanie L.
AU - Reed, Jason S.
AU - Bimber, Benjamin N.
AU - Greene, Justin M.
AU - Webb, Gabriela M.
AU - Northrup, Mina
AU - Laub, Wolfram
AU - Kievit, Paul
AU - MacAllister, Rhonda
AU - Axthelm, Michael K.
AU - Ducore, Rebecca
AU - Lewis, Anne
AU - Colgin, Lois M.A.
AU - Hobbs, Theodore
AU - Martin, Lauren D.
AU - Ferguson, Betsy
AU - Thomas, Charles R.
AU - Panoskaltsis-Mortari, Angela
AU - Meyers, Gabrielle
AU - Stanton, Jeffrey J.
AU - Maziarz, Richard T.
AU - Sacha, Jonah B.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-01631-z
DO - 10.1038/s41467-017-01631-z
M3 - Article
C2 - 29127275
AN - SCOPUS:85033605955
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1418
ER -