Bone marrow transplantation alters lung antigen-presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection

• Published in: Mucosal immunology Vol. 9; no. 3; pp. 610 - 620
• Main Authors: Zhou, X, Loomis-King, H, Gurczynski, S J, Wilke, C A, Konopka, K E, Ptaschinski, C, Coomes, S M, Iwakura, Y, van Dyk, L F, Lukacs, N W, Moore, B B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2016; Elsevier Limited
• Subjects: 631/250/1904; 631/250/21/1293; 631/250/251; 631/250/255/2514; Adoptive transfer; Allergology; Animals; Antibodies; Antibodies, Neutralizing - administration & dosage; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Biomedicine; Bone marrow; Bone Marrow Transplantation; CD11c antigen; CD4 antigen; Cells, Cultured; Disease Models, Animal; Early experience; Extracellular matrix; Fibrosis; Gastroenterology; Helper cells; Hematopoietic stem cells; Herpesviridae Infections - immunology; Humans; Immunology; Infections; Interleukin 12; Interleukin 23; Interleukin 6; Interleukin-17 - genetics; Interleukin-17 - immunology; Latency; Lung - pathology; Lymphocytes T; Mesenchyme; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; Pneumonia - etiology; Pneumonia - immunology; Pneumonia - prevention & control; Pneumonitis; Postoperative Complications - immunology; Postoperative Complications - prevention & control; Rhadinovirus - physiology; Stem cell transplantation; Syngeneic grafts; Th17 Cells - immunology; Th17 Cells - virology; Transforming growth factor-b; Viral infections; Virus Latency; Virus Replication; γ-Interferon
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2015.85

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-T
H
17 mRNAs for IL-23 and IL-6, and less T
H
1-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 T
H
1 response and suppresses aberrant T
H
17 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.