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 - Funding Information:
We thank Amgen, Inc. for providing Neulasta and Neupogen, Roger Wiseman and David O’Connor for assistance with MCM MHC typing, and Hans-Peter Kiem, Siriporn Tantawet, and Leslie Kean for helpful discussions on macaques undergoing HSCT. This research was funded by amfAR grant 108832 with support from FAIR (Foundation for AIDS Immune Research), R21 AI112433, R01 AI129703, and P51 OD011092.
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.
UR - http://www.scopus.com/inward/record.url?scp=85033605955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033605955&partnerID=8YFLogxK
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 -