Delayed Therapy with Receptor Tyrosine Kinase Inhibitor Nintedanib Diminished Chronic Rejection in a Murine Lung Transplant Model

Objectives: Previously we could show that the inhibitor of tyrosine kinase receptors nintedanib reduced the development of obliterative bronchiolitis (OB) after orthotopic trachea transplantation in a mouse model. After first analyses of delayed treatment, similar to the clinical situation after lung transplantation, the aim of this study was to further investigate the delayed nintedanib influence of inhibiting progression of chronic rejection in mouse trachea allografts

Methods: Allogenic donor trachea grafts from C57BL/6 mice (H2b) were transplanted into CBA mice (H2k) in orthotopic position (n = 8 per group). Afterward, recipients were set on nintedanib (60 mg/kg/d) either from day 1 or from day 14. In addition to histological measurements, cell infiltration investigations by immunofluorescence analyses were performed 30 days after transplantation for nintedanib-treated and -untreated control grafts. In addition, for all groups quantitative intragraft gene expression analyses of the receptors PDGFRα/β and VEGFR1/2 as well as of cytokines were performed 30 days after Tx.

Result: Delayed treatment with nintedanib led to a better epithelium lamina propria ratio compared with untreated animals (ELR delayed: 0.63 vs. 0.50 in untreated grafts; p < 0.05] and could be confirmed by additional data. Immunofluorescence analysis revealed significant less infiltration of CD4+ T cells and macrophages into tracheal allografts compared with untreated allografts (8.99 vs. 13.41; p < 0.01 [CD4+]; 14.94 vs. 25.21%; p < 0.05 [Mɸ]) as well as extenuated CD8+ T cells infiltrates (22.20 vs. 26.04% [CD8+]. The qPCR expression studies support a successful nintedanib blocking of the receptors PDGFRβ, VEGFR1, and VEGFR2 but not PDGFRα. Regardless, the expression of relevant mediators like PDGFβ, MCP-1, ICAM-1, and TGFβ was significant reduced in allografts of delayed treated compared with untreated mice.

Conclusion: These results demonstrate that even delayed treatment with nintedanib representative of a clinical setting and hence the subsequent blocking of tyrosine kinase receptors seems to be a promising tool to inhibit the development of chronic rejection in lung transplants.

Publication History

Article published online:
19 February 2021