title: Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production.
abstract: Allogeneic hematopoietic stem cell transplantation is hampered by chronic graft-versus-host disease (cGVHD), resulting in multiorgan fibrosis and diminished function. Fibrosis in lung and skin leads to progressive bronchiolitis obliterans (BO) and scleroderma, respectively, for which new treatments are needed. We evaluated pirfenidone, a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis, for its therapeutic effect in cGVHD mouse models with distinct pathophysiology. In a full major histocompatibility complex (MHC)-mismatched, multiorgan system model with BO, donor T-cell responses that support pathogenic antibody production are required for cGVHD development. Pirfenidone treatment beginning one month post-transplant restored pulmonary function and reversed lung fibrosis, which was associated with reduced macrophage infiltration and transforming growth factor-β production. Pirfenidone dampened splenic germinal center B-cell and T-follicular helper cell frequencies that collaborate to produce antibody. In both a minor histocompatibility antigen-mismatched as well as a MHC-haploidentical model of sclerodermatous cGVHD, pirfenidone significantly reduced macrophages in the skin, although clinical improvement of scleroderma was only seen in one model. In vitro chemotaxis assays demonstrated that pirfenidone impaired macrophage migration to monocyte chemoattractant protein-1 (MCP-1) as well as IL-17A, which has been linked to cGVHD generation. Taken together, our data suggest that pirfenidone is a potential therapeutic agent to ameliorate fibrosis in cGVHD.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Katelyn
authors.initials: K
authors.lastname: Paz
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Ryan
authors.initials: R
authors.lastname: Flynn
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD.
authors.forename: Ante
authors.initials: A
authors.lastname: Vulic
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Robinson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Meng
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
authors.forename: Sabita
authors.initials: S
authors.lastname: Roy
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Michael
authors.initials: M
authors.lastname: Loschi
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Serody
authors.affiliation: Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, MI.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA.
authors.forename: David
authors.initials: D
authors.lastname: Miklos
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Corey S
authors.initials: CS
authors.lastname: Cutler
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Kelli P
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, MN.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D064591:Allografts; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001989:Bronchiolitis Obliterans / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D011728:Pyridones / Q000494:pharmacology*; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C098680:Il17a protein, mouse; D020381:Interleukin-17; D011728:Pyridones; D016212:Transforming Growth Factor beta; C093844:pirfenidone