title: Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice.
abstract: Viral infection is a common, life-threatening complication after allogeneic bone marrow transplantation (BMT), particularly in the presence of graft-versus-host disease (GVHD). Using cytomegalovirus (CMV) as the prototypic pathogen, we have delineated the mechanisms responsible for the inability to mount protective antiviral responses in this setting. Although CMV infection was self-limiting after syngeneic BMT, in the presence of GVHD after allogeneic BMT, CMV induced a striking cytopathy resulting in universal mortality in conjunction with a fulminant necrotizing hepatitis. Critically, GVHD induced a profound dendritic cell (DC) defect that led to a failure in the generation of CMV-specific CD8(+) T-cell responses. This was accompanied by a defect in antiviral CD8(+) T cells. In combination, these defects dramatically limited antiviral T-cell responses. The transfer of virus-specific cells circumvented the DC defects and provided protective immunity, despite concurrent GVHD. These data demonstrate the importance of avoiding GVHD when reconstructing antiviral immunity after BMT, and highlight the mechanisms by which the adoptive transfer of virus-specific T cells overcome the endogenous defects in priming invoked by GVHD.
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Peter
authors.initials: P
authors.lastname: Fleming
authors.affiliation: Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; and.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Iona S
authors.initials: IS
authors.lastname: Schuster
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Valentina
authors.initials: V
authors.lastname: Voigt
authors.affiliation: Envoi Pathology, Brisbane, QLD, Australia.
authors.forename: Gregory
authors.initials: G
authors.lastname: Miller
authors.affiliation: Envoi Pathology, Brisbane, QLD, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; and.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; and.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA, Australia;
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology* / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology* / Q000821:virology; D005260:Female; D006086:Graft vs Host Disease / Q000150:complications* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL