title: The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.
abstract: Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.
authors: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
authors: H B
authors: HB
authors: Zheng
authors: Emory University School of Medicine, Atlanta, GA.
authors: B
authors: B
authors: Watkins
authors: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
authors: V
authors: V
authors: Tkachev
authors: Tulane National Primate Research Center, New Orleans, LA.
authors: S
authors: S
authors: Yu
authors: Tulane National Primate Research Center, New Orleans, LA.
authors: D
authors: D
authors: Tran
authors: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
authors: S
authors: S
authors: Furlan
authors: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.
authors: K
authors: K
authors: Zeleski
authors: Emory University School of Medicine, Atlanta, GA.
authors: K
authors: K
authors: Singh
authors: Emory University School of Medicine, Atlanta, GA.
authors: K
authors: K
authors: Hamby
authors: Washington National Primate Research Center, University of Washington, Seattle, WA.
authors: C
authors: C
authors: Hotchkiss
authors: Washington National Primate Research Center, University of Washington, Seattle, WA.
authors: J
authors: J
authors: Lane
authors: Emory University School of Medicine, Atlanta, GA.|Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA.
authors: S
authors: S
authors: Gumber
authors: Emory University School of Medicine, Atlanta, GA.
authors: A B
authors: AB
authors: Adams
authors: Department of Surgery, Duke University, Durham, NC.
authors: L
authors: L
authors: Cendales
authors: Department of Surgery, Duke University, Durham, NC.
authors: A D
authors: AD
authors: Kirk
authors: Tulane National Primate Research Center, New Orleans, LA.
authors: A
authors: A
authors: Kaur
authors: Department of Pediatrics, University of Minnesota, Minneapolis, MN.
authors: B R
authors: BR
authors: Blazar
authors: Emory University School of Medicine, Atlanta, GA.
authors: C P
authors: CP
authors: Larsen
authors: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: L S
authors: LS
authors: Kean
mesh_terms: D000818:Animals; D003141:Communicable Diseases / Q000209:etiology / Q000473:pathology; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000150:complications* / Q000276:immunology / Q000821:virology; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D008253:Macaca mulatta; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D014775:Virus Activation / Q000276:immunology*
keywords: animal models: nonhuman primate; bone marrow/hematopoietic stem cell transplantation; tolerance: chimerism; translational research/science