title: Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells.
abstract: One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graft-versus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease.
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Scott N
authors.identifier: 0000-0003-3007-9840
authors.initials: SN
authors.lastname: Furlan
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Watkins
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Victor
authors.initials: V
authors.lastname: Tkachev
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Sarah
authors.identifier: 0000-0001-8953-6730
authors.initials: S
authors.lastname: Cooley
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Kayla
authors.initials: K
authors.lastname: Betz
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Brown
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hunt
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: John B
authors.initials: JB
authors.lastname: Schell
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Katie
authors.initials: K
authors.lastname: Zeleski
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Alison
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Giver
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA.|Department of Pediatrics, University of Washington, Seattle, WA.|Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000882:Haplorhini; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy; D020381:Interleukin-17 / Q000276:immunology*; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology
chemical_list: D020381:Interleukin-17