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IL-17A contributes to lung fibrosis in a model of chronic pulmonary graft-versus-host disease

Martinu, Tereza MD1,2,*; McManigle, William C MD2,*; Kelly, Francine L BS2; Nelson, Margaret E BS2; Sun, Jesse MD2; Zhang, Helen L MD2; Kolls, Jay K MD3; Gowdy, Kymberly M PhD4; Palmer, Scott M MD MHS2

doi: 10.1097/TP.0000000000002837
Basic Science-General: PDF Only

Background: Chronic pulmonary graft-versus-host disease (cpGVHD) after hematopoietic cell transplant (HCT) manifests as progressive airway and parenchymal lung fibrosis. Based on 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.

Methods: AlloTbet-/- mice received weekly intraperitoneal anti-IL-17A or IgG (200μg/mouse) starting 2 weeks post-HCT and were sacrificed after week 5. Histologic airway and parenchymal fibrosis was semi-quantitatively graded in a blinded fashion. Lung cells and proteins were measured by flow cytometry, ELISA, and multi-cytokine assays.

Results: 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.

Conclusions: 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 and/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.

1Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada

2Department of Internal Medicine, Duke University, Durham, NC, USA

3Department of Internal Medicine, Center for Translational Research in Infection and Inflammation, Tulane School of Medicine, New Orleans, LA, USA

4Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

* First two authors contributed equally.

Disclosure: The authors of this manuscript have no conflicts of interest to disclose.

Funding: Funding was provided by NIH / NHLBI 1P50-HL084917-01 (SCCOR) (to SMP, TM, KG), NIH 1 K24 HL91140-01A2 (to SMP), Lung Transplant Foundation (to SMP), ISHLT Norman E. Shumway Career Development Award (to TM), and Steadman award (to WCM)

Corresponding Author: Tereza Martinu, Address: 585 University Avenue, PMB 11-128, Toronto, ON Canada M5G 2N2, Email:

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