P012. Vidofludimus inhibits IL‑17 and improves hapten-induced colitis in young rats by a unique dual mode of action
L.R. Fitzpatrick1, J.S. Small1, R. Doblhofer2, S.W. Henning2, A. Ammendola2
1Penn State College of Medicine, Department of Pharmacology, Hummelstown, United States; 24SC AG, Planegg-Martinsried, Germany
Background: Vidofludimus (Vido), an inhibitor of DHODH and interleukin-17 (IL‑17A and IL‑17F), is a novel oral immunomodulator in clinical phase II for IBD. Previously we showed that IL‑17 inhibition by Vido in vitro is decoupled from its effects on lymphocyte proliferation (Fitzpatrick et al., Inflam Bowel Dis, 2010). The aim of this study was to evaluate the in vivo effects of Vido on IL‑17 expression and colitis symptoms, in the presence or absence of concomitant uridine (Ur) dosing, by using our rat model of hapten-induced colitis (Fitzpatrick et al., JPGN, 2010).
Methods: Young Wistar rats were dosed with either vehicle(s) (Phosal 50 PG [p.o.] or 0.9% saline [i.p.]), Ur (500 mg/kg, i.p.), Vido (60 mg/kg, p.o.), or Vido + Ur for a six day period (days 0 to 5). On day 1, rats received a 150 µL enema of either PBS or TNBS (8 mg in 40% Ethanol/PBS). On day 6 various morphometric, biochemical and histological indices of colitis were determined from the colonic tissue. Macroscopic colonic scores included observations on ulceration, adhesions, colonic thickness and diarrhea. IL‑17 levels and STAT3 activation were measured with commercial ELISA kits and myeloperoxidase (MPO) was analyzed by the tetramethylbenzidine method. Histological scores and numbers of CD3+ T‑cells (by immuno-histochemistry) were determined using coded slides.
Results: On study day 6, macroscopic colonic scores were: 0.8±0.8 (vehicle/PBS), 125±31 (vehicle/TNBS), 43±17 (Vido/TNBS), 124±34 (Ur/TNBS) and 72±26 (Vido + Ur/TNBS). A similar data pattern was found for colonic histology scores and CD3+ T‑cells in the lamina propria/submucosa (p < 0.05 vs. vehicle/TNBS with Vido or Vido + Ur treatments). In contrast, similarly reduced nuclear STAT3 binding, IL‑17 and MPO levels were observed in colonic samples from animals treated with Vido alone and Vido + Ur.
Conclusions: Vido improved parameters of TNBS-induced colitis in young rats, including macroscopic pathology and colonic CD3+ T‑cells. Vido treatment, in the presence of Ur, also improved these parameters, but not to the same degree as Vido alone. Of note, colonic STAT3 binding and IL‑17 inhibition by Vido was not affected by combination with Ur. Thus, Vido appears to improve colonic inflammation by a dual mode of action, namely inhibition of T‑cell proliferation and suppression of pro-inflammatory cytokines which is decoupled from the control of proliferation. This unique pharmacological profile supports further clinical testing of Vido in patients with IBD.