Journal Article

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

Webb, Gabriela M., Junell, Stephanie L., Meyers, Gabrielle, Lewis, Anne, Thomas Jr, Charles R., Hammond, Katherine B., Wu, Helen L., Bimber, Benjamin N., Ducore, Rebecca, Shriver-Munsch, Christine, Laub, Wolfram, Axthelm, Michael K., Hobbs, Theodore, Colgin, Lois M. A., Panoskaltsis-Mortari, Angela, Sacha, Jonah B., Legasse, Alfred W., Northrup, Mina, Martin, Lauren D., Maziarz, Richard T., Burwitz, Benjamin J., Reed, Jason S., Ferguson, Betsy, Stanton, Jeffrey J., Swanson, Tonya, Greene, Justin M., Abdulhaqq, Shaheed, MacAllister, Rhonda, Kievit, Paul

2017

Overview

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. Rhesus macaques are not ideal for studying response to allogeneic hematopoietic stem cell transplant (allo-HSCT) owing to complex MHC genetics that prevent full MHC-matching. Here the authors show that inbred Mauritian-origin cynomolgus macaques are a superior preclinical model of allogeneic stem cell transplantation that mimics diverse clinical outcomes of human allo-HSCT.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250/1854/2812 / 631/250/255 / Animals / CD28 antigen / Chimerism / Clinical outcomes / Cyclophosphamide / Disease control / Disease prevention / Female / Graft rejection / Graft vs Host Disease - prevention & control / Graft-versus-host reaction / Grafting / Grafts / Hematology / Hematopoietic Stem Cell Transplantation - methods / Histocompatibility Testing / HIV / Human immunodeficiency virus / Humanities and Social Sciences / Humans / Immunity / Immunodeficiency / Immunological tolerance / Inborn errors of metabolism / Macaca fascicularis - genetics / Macaca fascicularis - immunology / Major Histocompatibility Complex / Male / Metabolism / Models, Animal / multidisciplinary / Peripheral blood / Science / Science (multidisciplinary) / Species Specificity / Stem cell transplantation / Stem cells / Tacrolimus / Transplantation / Transplantation Chimera - genetics / Transplantation Chimera - immunology / Transplantation Tolerance - genetics / Transplantation Tolerance - immunology / Transplantation, Homologous / Transplants & implants / Treatment Outcome