title: Bone marrow transplantation alters lung antigen-presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection.
abstract: Hematopoietic stem cell transplantation (HSCT) efficacy is limited by numerous pulmonary complications. We developed a model of syngeneic bone marrow transplantion (BMT) followed by infection with murine gamma herpesvirus-68 that results in pneumonitis and fibrosis and mimics human "noninfectious" HSCT complications. BMT mice experience increased early lytic replication, but establish viral latency by 21 days post infection. CD4 T cells in BMT mice are skewed toward interleukin (IL)-17A rather than interferon (IFN)-γ production. Transplantation of bone marrow from Il-17a(-/-) donors or treatment with anti-IL-17A neutralization antibodies at late stages attenuates pneumonitis and fibrosis in infected BMT mice, suggesting that hematopoietic-derived IL-17A is essential for development of pathology. IL-17A directly influences activation and extracellular matrix production by lung mesenchymal cells. Lung CD11c+ cells of BMT mice secrete more transforming growth factor beta-β1, and pro-TH17 mRNAs for IL-23 and IL-6, and less TH1-promoting cytokine mRNA for IFN-γ but slightly more IL-12 mRNA in response to viral infection. Adoptive transfer of non-BMT lung CD11c-enriched cells restores robust TH1 response and suppresses aberrant TH17 response in BMT mice to improve lung pathology. Our data suggest that "noninfectious" HSCT lung complications may reflect preceding viral infections and demonstrate that IL-17A neutralization may offer therapeutic advantage even after disease onset.
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: H
authors.initials: H
authors.lastname: Loomis-King
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Gurczynski
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Wilke
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Konopka
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ptaschinski
authors.affiliation: Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Coomes
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: van Dyk
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: N W
authors.initials: NW
authors.lastname: Lukacs
authors.affiliation: Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: B B
authors.initials: BB
authors.lastname: Moore
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D006566:Herpesviridae Infections / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D011183:Postoperative Complications / Q000276:immunology* / Q000517:prevention & control; D018144:Rhadinovirus / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology* / Q000821:virology; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D020381:Interleukin-17