Chronic pulmonary graft-versus-host disease (cpGVHD) after hematopoietic cell transplant (HCT) manifests as progressive airway and parenchymal lung fibrosis. On the basis of our prior data, mice that undergo allogeneic HCT with Tbet-knockout donors (AlloTbet−/−) have increased lung Th17 cells and IL-17A and develop fibrosis resembling human cpGVHD. The role of IL-17A in posttransplant pulmonary fibrosis remains incompletely understood. We hypothesized that IL-17A is necessary for development of murine cpGVHD in this model.
AlloTbet−/− mice received weekly intraperitoneal anti-IL-17A or IgG (200 μg/mouse) starting 2 weeks post-HCT and were sacrificed after week 5. Histologic airway and parenchymal fibrosis were semiquantitatively graded in a blinded fashion. Lung cells and proteins were measured by flow cytometry, ELISA, and multicytokine assays.
Anti-IL-17A modestly decreased airway and parenchymal lung fibrosis, along with a striking reduction in pulmonary neutrophilia, IL-6, MIP-1α, MIP-1β, CXCL1, and CXCL5 in AlloTbet−/− mice. Additionally, anti-IL-17A decreased CCL2, inflammatory monocytes and macrophages, and Th17 cells.
In the setting of murine AlloHCT with Tbet−/− donors, IL-17A blockade decreases fibrotic features of cpGVHD. This may be mediated by the observed reduction in neutrophils or specific lung monocyte and macrophage populations or alternatively via a direct effect on fibroblasts. Collectively, our results further suggest that anti-IL-17A strategies could prove useful in preventing alloimmune-driven fibrotic lung diseases.
1 Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.
2 Department of Internal Medicine, Duke University, Durham, NC.
3 Department of Internal Medicine, Center for Translational Research in Infection and Inflammation, Tulane School of Medicine, New Orleans, LA.
4 Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC.
Received 3 January 2019. Revision received 25 April 2019.
Accepted 8 May 2019.
T.M. and W.C.M. contributed equally. T.M., W.C.M., J.K.K., K.M.G., and S.M.P. conceived and designed the research project. T.M., W.C.M., K.M.G., F.L.K., M.E.N., J.S., and H.L.Z. participated in performance of experiments. T.M., W.C.M., F.L.K., M.E.N., J.S., H.L.Z., K.M.G., and S.M.P. performed analysis and interpretation of data. T.M., W.C.M., J.K.K., K.M.G., and S.M.P. participated in writing of the manuscript.
The authors declare no conflicts of interest.
Funding was provided by NIH/NHLBI 1P50-HL084917-01 (SCCOR) (to S.M.P., T.M., and K.M.G.), NIH 1 K24 HL91140-01A2 (to S.M.P.), Lung Transplant Foundation (to S.M.P.), ISHLT Norman E. Shumway Career Development Award (to T.M.), and Steadman award (to W.C.M.).
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Correspondence: Tereza Martinu, MD, 585 University Ave, PMB 11–128, Toronto, ON M5G 2N2, Canada. (firstname.lastname@example.org).