Tanimilast is a novel, highly potent and selective inhaled phosphodiesterase-4 (PDE4) inhibitor in advanced clinical development for the treatment of COPD. Since IL-17 response has been associated with neutrophilic inflammation and COPD progression, we investigated the potential effect of tanimilast on human lymphocytes under different in vitro T17-promoting conditions.

PBMC isolated from healthy volunteers were stimulated under TCR-dependent or TCR-independent conditions. In parallel, naïve CD4+CD45RA+ T cells were magnetically sorted from blood of healthy donors and de novo differentiated to Th17 cells. Both PBMC and naïve T cells were treated with tanimilast or a selective ROR?t inverse agonist, as control, before stimulation. FACS analysis and Meso Scale Discovery technology were used for cell population analysis and cytokines dosage, respectively.

Tanimilast reduced the IL-17A release in PBMC stimulated both in TCR- dependent and TCR-independent conditions (IC50=150nM, IC50=200nM, respectively). Moreover, tanimilast showed to be more potent (IC50=10nM) in reducing the IL-17A release in naive CD4+ T lymphocytes under de novo Th17 differentiating conditions than in whole PBMC population.

These data suggest that PDE4 inhibition could represent an effective strategy targeting T17 response. Tanimilast could act directly on newly differentiating Th17 cells, thus preventing further amplification of pre-existing inflammatory responses.