INTESTINAL SIDE-EFFECTS OF IFNα2a (ROFERON) ARE MEDIATED by the ACTIVATION of MUCOSAL T LYMPHOCYTES and the ONSET of a Th1 RESPONSE

IFNα2a, a subtype of IFN type I, plays an important role in innate immunity. In the clinics, IFNα2a, called Roferon, part of the treatment of various diseases, has side-effects including intestinal disorders. The aim of this work was to explore the potential deleterious effects of IFNα2a on intestinal mucosa homeostasis, using an ex vivo 3-D model system of human normal colonic mucosa explant culture. We showed that treatment of 24h explant cultures with IFNα2a dose-dependently induced a marked alteration of the surface colonic epithelium and crypt base, through an apoptotic process. In addition, IFNα2a i) elicited a dose-dependent IFNΥ response, associated with an IL-18 response, variable among individuals, and ii) strongly increased the number of Tbet+ lamina propria lymphocytes. Furthermore, a pharmacological approach demonstrated that both the IFNα-induced Th1 response and epithelial damage were subordinated to the inflammasome (caspase-1 / IL18) pathway. Finally, preliminary experiments, both ex vivo and in vitro, strongly suggested that the epithelial barrier apoptosis resulted from the IFNα-mediated Th1 (IFNΥ) response. Altogether, these findings provide the first demonstration that the intestinal side-effects of Roferon can be accounted for by epithelial barrier disruption via the activation of mucosal T lymphocytes and the onset of a Th1 response.