Halofuginone treatment reduces interleukin-17A and ameliorates features of chronic lung allograft dysfunction in a mouse orthotopic lung transplant model

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• 作者：Hisashi Oishi ; MD ; PhD^a ; Tereza Martinu ; MD^a ; Masaaki Sato ; MD ; PhD^a ; ^b ; Yasushi Matsuda ; MD ; PhD^c ; Shin Hirayama ; MD ; PhD^d ; Stephen C. Juvet ; MD ; PhD^a ; Zehong Guan^a ; Tomohito Saito ; MD ; PhD^e ; Marcelo Cypel ; MD ; MSc^a ; David M. Hwang ; MD ; PhD^a ; Tracy L. Keller ; PhD^f ; Malcolm R. Whitman ; PhD^f ; Mingyao Liu ; MD ; MSc^a ; Shaf Keshavjee ; MD ; MSc^a ; ^{shaf.keshavjee@uhn.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：chronic lung allograft dysfunction ; halofuginone ; IL-17 ; obliterative bronchiolitis ; restrictive allograft syndrome
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：35
• 期：4
• 页码：518-527
• 全文大小：9844 K

文摘

Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigen‒mismatched mouse orthotopic lung transplant model.

Methods

C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 μg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant.

Results

Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p < 0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p < 0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17A‒positive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-β1 and matrix metalloproteinase-2 transcripts at Days 14 and 28.

Conclusion

The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.