Nintedanib inhibits pro-fibrotic mediators from T cells with relevance to connective tissue disease-associated interstitial lung disease

Abstract

<b>Rationale:</b> Interstitial lung disease (ILD) in patients with connective tissue diseases (CTD) like systemic sclerosis (SSc) or rheumatoid arthritis (RA) is strongly associated with mortality. T cells appear to play a prominent role in the pathogenesis of SSc and RA. T cells release pro-fibrotic mediators stimulating fibroblasts that serve to drive the fibrotic response. Nintedanib is approved for the treatment of IPF in many countries. Nintedanib is a receptor tyrosine kinase inhibitor with specificity for FGFR 1-3, VEGFR 1-3, PDGFRα and β and SRC family kinases like Src, Lyn and Lck. Lck is required for signal transduction through the T cell receptor and involved in pro-fibrotic mediator release. The objective of this study was to determine the inhibitory potency of nintedanib on pro-fibrotic mediator release of T cells. <b>Methods:</b> Human T cells and CD4⁺ and CD8⁺ subsets were incubated with nintedanib (0.1 – 1000 nM) and stimulated for 24 h with anti-CD3 or anti-CD3/anti-CD28. Supernatants were collected and IFNγ, IL-2, IL-4, IL-5, IL-10, IL12p70 and IL-13 were detected. <b>Results:</b> Nintedanib blocked the release of IFNγ, IL-2, IL-4, IL-5, IL-10, IL12p70 and IL-13 from T cells and IL-2 from CD4⁺ and CD8⁺ subsets in a concentration-dependent manner with IC₅₀ values ranging from 5 to 83 nmol/L. The IC₅₀ values are within or close to the maximum exposure of nintedanib in patients (~70 nmol/L). <b>Conclusion:</b> Reductions in immune-stimulating and pro-fibrotic mediators might contribute to clinical efficacy of nintedanib in SSc-ILD or RA-ILD. A clinical trial to explore the efficacy of nintedanib in patients with SSc-ILD is ongoing (SENSCIS trial, NCT02597933).