The activity of nintedanib in a mouse model of severe allergic lung remodeling

Wollin, Lutz; Tomsic, Christopher; Erb, Klaus J.

doi:10.1183/13993003.congress-2018.pa4797

Cited by 1 publication

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17,21,22 It also demonstrated a reduction in fibrosis and inflammation in different animal models of lung fibrosis. [22][23][24][25][26] However, the underlying mechanisms by which nintedanib targets pulmonary fibrosis via T cells have not been explored. We know that T-cell activation is dependent on T-cell antigen receptor (TCR) signaling, which is initiated through the phosphorylation of several tyrosine kinases, such as Src and Lck, 27,28 and dampened by the phosphorylation of Fyn.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Nintedanib on T-Cell Activation, Subsets and Functions

Ubieta¹,

Thomas²,

Wollin³

2021

DDDT

Self Cite

View full text Add to dashboard Cite

Background T cells are important regulators of inflammation and, via release of mediators, can contribute to pulmonary fibrosis. Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease (ILD) and chronic fibrosing ILDs with a progressive phenotype. However, how nintedanib targets T cells has not been elucidated. Materials and Methods We investigated the immunomodulatory effects of nintedanib on T cells and peripheral blood mononuclear cells isolated from healthy donors. Cells were pre-incubated with different concentrations of nintedanib and then stimulated for 24 hours with anti-CD3 with or without anti-CD28 and with or without different cytokines. Levels of interferon gamma (IFN-γ), interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 were quantitated. Western blotting with primary antibodies against phospho-Lck-Y394, phospho-Lck-Y505, Lck-total and Cofilin examined the phosphorylation level of the Lck protein. In vitro T-cell proliferation, T-cell clustering and different T-cell populations were also assessed. Results Nintedanib blocked T-cell activation through inhibiting Lck-Y394 phosphorylation. Pretreatment of T cells with nintedanib reduced cluster formation as a marker of activation and inhibited the release of IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12p70 and IL-13 at clinically relevant concentrations ranging from 5–77 nmol/L. Nintedanib did not alter T-cell proliferation or numbers of CD4+ and CD8+ T cells, but did increase stimulated Th17-like cells without increasing IL-17A levels. Conclusion These immunomodulatory effects may further explain how nintedanib slows the progression of pulmonary fibrosis in various ILDs.

show abstract