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P013. Vidofludimus induces p53-mediated apoptosis in activated T cells and inhibits IL‑17A and IL‑17F expression decoupled from lymphocyte proliferation

S. Hamm1, S.W. Henning1, B. Hentsch1, D. Vitt1, M. Groeppel1, A. Ammendola1

14SC AG, Planegg-Martinsried, Germany

Background: Vidofludimus is a novel oral immunomodulator that has shown substantial activity in various autoimmune models and is currently clinically developed for inflammatory bowel disease (IBD). Induction of apoptosis in mucosal T cells from IBD patients is a relevant therapeutic mechanism since several effective IBD drugs like 6‑mercaptopurine (6-MP) were shown to induce apoptosis in activated T cells. The interleukin-17 (IL‑17) cytokine family is involved in many inflammatory diseases and increased IL‑17 levels have been found in inflamed gut mucosa and serum of IBD patients. Especially IL‑17F plays a crucial role in the pathogenesis of IBD. Vidofludimus has been described to inhibit IL‑17A and IL‑17F in vitro and in vivo in IBD models. In this study the apoptosis inducing capacity of vidofludimus and its inhibitory effect on IL‑17 expression by activated T cells in relation to its effect on cell proliferation have been investigated.

Methods: PBMC isolated from blood of healthy volunteers and stimulated with phytohaemagglutinin (PHA) were analyzed for cell cycle arrest, IL‑17 expression, cell proliferation (BrdU incorporation), and apoptosis induction (AnnexinV/PI staining) by flow cytometry. P53 accumulation was measured by ELISA, IL‑17A and IL‑17F gene expression by RT-PCR. Apoptosis induction was also analyzed in Jurkat cells.

Results: Vidofludimus is a potent inducer of apoptosis in PHA activated T cells and Jurkat cells, comparable to reference compound 6‑MP. The active metabolite of leflunomide was less active, particularly in Jurkat cells. G1/S arrest and strong accumulation of p53 precede apoptosis induction. Vidofludimus inhibits production of IL‑17AA/AF and IL‑17FF in a dose-dependent fashion with IC50 values between 3 and 10 µM; this correlates well with reduced gene expression patterns for IL‑17 subtypes 20 h after PHA stimulation. This effect is decoupled from T cell proliferation as significant inhibition of IL‑17 production is observed already 24 h after stimulation whereas inhibition of T cell proliferation by vidofludimus as judged by BrdU incorporation is not detectable earlier than 48 h after activation.

Conclusions: Vidofludimus induces cell cycle arrest, p53 accumulation and subsequent apoptosis in activated T cells. Furthermore, it inhibits production of IL‑17 cytokines decoupled from its effects on T cell proliferation. The combination of both effects might substantially contribute to the beneficial effects of vidofludimus observed in IBD patients as previously reported.