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

Autor: Charles R. Thomas, Jeffrey J. Stanton, Jason S. Reed, Gabrielle Meyers, Mina Northrup, Katherine B. Hammond, Helen L. Wu, Stephanie L. Junell, Anne D. Lewis, Shaheed A. Abdulhaqq, Paul Kievit, Benjamin J. Burwitz, Theodore R. Hobbs, Alfred W. Legasse, Lauren D. Martin, W Laub, Gabriela M. Webb, Betsy Ferguson, Rebecca M. Ducore, Michael K. Axthelm, Justin M. Greene, Jonah B. Sacha, Lois M. A. Colgin, Tonya Swanson, Richard T. Maziarz, Angela Panoskaltsis-Mortari, Christine Shriver-Munsch, Benjamin N. Bimber, Rhonda MacAllister
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Cyclophosphamide
Science
medicine.medical_treatment
Graft vs Host Disease
General Physics and Astronomy
chemical and pharmacologic phenomena
Hematopoietic stem cell transplantation
Article
General Biochemistry
Genetics and Molecular Biology
Major Histocompatibility Complex
03 medical and health sciences
0302 clinical medicine
Species Specificity
immune system diseases
Immunity
medicine
Animals
Humans
Transplantation
Homologous
lcsh:Science
Immunodeficiency
Transplantation Chimera
Multidisciplinary
business.industry
Histocompatibility Testing
Hematopoietic Stem Cell Transplantation
General Chemistry
medicine.disease
Tacrolimus
3. Good health
Transplantation
Macaca fascicularis
Treatment Outcome
surgical procedures
operative
030104 developmental biology
Models
Animal
Immunology
Female
Transplantation Tolerance
lcsh:Q
Stem cell
business
030215 immunology
Allotransplantation
medicine.drug
Zdroj: Nature Communications, Vol 8, Iss 1, Pp 1-10 (2017)
Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-017-01631-z
Popis: 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.
Databáze: OpenAIRE
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