IL-17A Contributes to Lung Fibrosis in a Model of Chronic Pulmonary Graft-versus-host Disease.

Abstract

BACKGROUND:

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.

METHODS:

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.

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 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.

• Authors: Tereza Martinu, William C McManigle, Francine L Kelly, Margaret E Nelson, Jesse Sun, Helen L Zhang, Jay K Kolls, Kymberly M Gowdy, Scott M Palmer
• Journal: Transplantation (Transplantation) Vol. 103 Issue 11 Pg. 2264-2274 (11 2019) ISSN: 1534-6080 [Electronic] United States
• PMID: 31658231 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Ccl3 protein, mouse
• Ccl4 protein, mouse
• Chemokine CCL2
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CXCL1
• Chemokine CXCL5
• Cxcl1 protein, mouse
• Cxcl5 protein, mouse
• Il17a protein, mouse
• Interleukin-17
• Interleukin-6

Topics

• Animals
• Chemokine CCL2 (blood)
• Chemokine CCL3 (blood)
• Chemokine CCL4 (blood)
• Chemokine CXCL1 (blood)
• Chemokine CXCL5 (blood)
• Chronic Disease
• Graft vs Host Disease (pathology)
• Hematopoietic Stem Cell Transplantation
• Inflammation
• Interleukin-17 (antagonists & inhibitors, immunology)
• Interleukin-6 (blood)
• Lung (immunology, physiopathology)
• Macrophages (cytology)
• Male
• Mice
• Mice, Inbred C57BL
• Monocytes (cytology)
• Pulmonary Fibrosis (physiopathology)