期刊
MUCOSAL IMMUNOLOGY
卷 9, 期 3, 页码 610-620出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2015.85
关键词
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类别
资金
- NIH [AI117229, HL115618]
- MICHR [2UL1TR000433]
- [T32HL07749]
- [T32 AI007413]
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)-gamma 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-beta 1, and pro-T(H)17 mRNAs for IL-23 and IL-6, and less T(H)1-promoting cytokine mRNA for IFN-gamma 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.
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