CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.
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-β) 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.
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California. Electronic address: shirin.birjandi@cshs.org.
Shirin Z
SZ
Birjandi
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Vyacheslav
V
Palchevskiy
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Ying Ying
YY
Xue
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Stefanie
S
Nunez
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Rita
R
Kern
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
S Sam
SS
Weigt
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Joseph P
JP
Lynch
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Talal A
TA
Chatila
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
John A
JA
Belperio
D019264:Adoptive Transfer; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin