Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production

Jing Du, Katelyn Paz, Ryan Flynn, Ante Vulic, Tara Robinson, Katie E. Lineburg, Kylie A. Alexander, Jingjing Meng, Sabita Roy, Angela Panoskaltsis-Mortari, Michael Loschi, Geoffrey R. Hill, Jonathan S. Serody, Ivan Maillard, David Miklos, John Koreth, Corey S. Cutler, Joseph H. Antin, Jerome Ritz, Kelli P. MacDonald & 3 others Timothy W. Schacker, Leo Luznik, Bruce R. Blazar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2570-2580
Number of pages11
JournalBlood
Volume129
Issue number18
DOIs
StatePublished - May 4 2017

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Macrophages
Graft vs Host Disease
Infiltration
Grafts
Fibrosis
Bronchiolitis Obliterans
Major Histocompatibility Complex
Lung
Skin
Transplantation (surgical)
Idiopathic Pulmonary Fibrosis
Transplants
Histocompatibility
Germinal Center
T-cells
Interleukin-17
Antibodies
Chemokine CCL2
Hematopoietic Stem Cell Transplantation
Transforming Growth Factors

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production. / Du, Jing; Paz, Katelyn; Flynn, Ryan; Vulic, Ante; Robinson, Tara; Lineburg, Katie E.; Alexander, Kylie A.; Meng, Jingjing; Roy, Sabita; Panoskaltsis-Mortari, Angela; Loschi, Michael; Hill, Geoffrey R.; Serody, Jonathan S.; Maillard, Ivan; Miklos, David; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Ritz, Jerome; MacDonald, Kelli P.; Schacker, Timothy W.; Luznik, Leo; Blazar, Bruce R.

In: Blood, Vol. 129, No. 18, 04.05.2017, p. 2570-2580.

Research output: Contribution to journalArticle

Du, J, Paz, K, Flynn, R, Vulic, A, Robinson, T, Lineburg, KE, Alexander, KA, Meng, J, Roy, S, Panoskaltsis-Mortari, A, Loschi, M, Hill, GR, Serody, JS, Maillard, I, Miklos, D, Koreth, J, Cutler, CS, Antin, JH, Ritz, J, MacDonald, KP, Schacker, TW, Luznik, L & Blazar, BR 2017, 'Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production', Blood, vol. 129, no. 18, pp. 2570-2580. https://doi.org/10.1182/blood-2017-01-758854
Du, Jing ; Paz, Katelyn ; Flynn, Ryan ; Vulic, Ante ; Robinson, Tara ; Lineburg, Katie E. ; Alexander, Kylie A. ; Meng, Jingjing ; Roy, Sabita ; Panoskaltsis-Mortari, Angela ; Loschi, Michael ; Hill, Geoffrey R. ; Serody, Jonathan S. ; Maillard, Ivan ; Miklos, David ; Koreth, John ; Cutler, Corey S. ; Antin, Joseph H. ; Ritz, Jerome ; MacDonald, Kelli P. ; Schacker, Timothy W. ; Luznik, Leo ; Blazar, Bruce R. / Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-β production. In: Blood. 2017 ; Vol. 129, No. 18. pp. 2570-2580.
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AU - Alexander, Kylie A.

AU - Meng, Jingjing

AU - Roy, Sabita

AU - Panoskaltsis-Mortari, Angela

AU - Loschi, Michael

AU - Hill, Geoffrey R.

AU - Serody, Jonathan S.

AU - Maillard, Ivan

AU - Miklos, David

AU - Koreth, John

AU - Cutler, Corey S.

AU - Antin, Joseph H.

AU - Ritz, Jerome

AU - MacDonald, Kelli P.

AU - Schacker, Timothy W.

AU - Luznik, Leo

AU - Blazar, Bruce R.

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N2 - 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.

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