Small Molecule Tyrosine Kinase Inhibitor Nintedanib Reduces Development of Transplant Vasculopathy in a Murine Aortic Transplantation Model

Background: Nintedanib is an intracellular inhibitor of several receptor tyrosine kinases and blocks signal transduction of growth factors like platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). All of these growth factors are of significance in the context of transplant vasculopathy. Therefore the aim of this study was to determine the impact of tyrosine kinase inhibition by nintedanib on the development of transplant vasculopathy in a mouse model.

Methods: Orthotopic aortic transplantation was performed in a fully allogeneic mouse model (C57BL/6 (H2^b) in CBA (H2^k)). Recipients were treated with tyrosine kinase inhibitor nintedanib (60mg/kg/d), and sacrificed on day 14 for cytokine PCR analysis of the graft or on day 30 for (immuno-) histological measurements.

Results: After 30 days of nintedanib treatment aortic grafts showed significantly less neointima proliferation (33% ± 12% vs. 54% ± 13%) with a markedly reduced percentage of smooth muscle cells (20% ± 9% vs. 42% ± 10%) in the neointima. The expression of both PDGF receptor subtypes α and β was significantly reduced within the neointima of the aortic grafts. Additionally, we found a reduced amount of the ligand PDGF-B. Interestingly, the expression of VEGF- and FGF-receptors did not differ in the graft with and without nintedanib treatment.

Conclusion: Blockade of receptor tyrosine kinases seems to be a promising way to inhibit the development of transplant vasculopathy after vessel transplantation in a mouse model. As the mechanism of action we speculate a direct inhibition of the migration and proliferation of smooth muscle cells with resulting decreased neointima formation.

No conflict of interest has been declared by the author(s).