期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 8, 页码 2008-2020出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2016.03.020
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资金
- NIH Pulmonary Training grant [T32HL07252]
- National Center for Advancing Translational Sciences through UCLA CTSI grant [UL1 TR000124]
- NIH [R01 HL112990, HL131407, CTOT 11532596, 2R01AI065617]
Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used in vivo to expand CD4(+)CD25(hi)Foxp3(+) cells in the lung during intratracheal bleomycin challenge; however, this unexpectedly led to an increase in lung fibrosis. More important, this increase in fibrosis was a lymphocyte dependent process. We corroborated these results using a CD4(+)CD25(hi)Foxp3(+) cellular -based therapy. Mechanistically, we demonstrated that CD4(+)CD25(hi)Foxp3(+) cells undergo alterations during bleomycin challenge and the IL-2 complex had no effect on profibrotic (eg, transforming growth factor-beta or type 17 immune response cytokines; however, there was a marked down-regulation of the type 1 and augmentation of the type 2 immune response cytokines from the lungs. Collectively, our animal studies show that a specific lung injury can induce Treg alterations, which can augment pulmonary fibrosis.
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