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

Abstract

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.

Nintedanib reduces corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice by increasing the expression of β3 & β6 integrins

“…IL-4 act directly on lung broblast to induce a bro-genic response. However, IFN-γ, which is also reduced by nintedanib, exhibits potent anti brotic activity by inhibiting synthesis of collagen in broblasts (Ubieta et al, 2021). Moreover, the oxidative stress is de ned as extra production of reactive oxygen species (ROS) or decreases in antioxidants.…”

Role of antifibrotics in the management of idiopathic inflammatory myopathy associated interstitial lung disease

“…Interestingly, proliferation was unaffected. 56 – 59 Additional work is needed to understand whether nintedanib is immunomodulatory in vivo .…”

Systemic Sclerosis Associated Interstitial Lung Disease and Nintedanib: A Rare Disease and a Promising Drug

“…Nintedanib improved fibrosis in these mice models by inhibiting different cytokines such as TGF-B and PDGF, the essential mediators in activating lung fibroblasts [ 14 ]. Nintedanib has also shown its immunomodulatory effects by blocking T-cell stimulation [ 15 ].…”