Itraconazole ameliorates graft-versus-host disease in mice by modulating Th17 responses and STAT3 signaling.
TL;DR
Itraconazole is shown that itraconazole ameliorates GVHD and is associated with reduced phosphorylated STAT3 (pSTAT3) levels and decreased Th17 cell differentiation, suggesting itraconazole may have potential to ameliorate GVHD and tissue damage.
Abstract
Background The resolution of graft-versus-host disease (GVHD) improves survival of patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper 17 (Th17) cells mediate the progression and severity of GVHD. The differentiation of Th17 cells relies on the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which activates the transcription factor retinoic acid-related orphan receptor γt (RORγt), consolidating the fate of the cell. In this study, we aim to investigate the prophylactic efficacy of itraconazole in GVHD. Methods In this study, T cell proliferation and effector T cell subtypes were assessed after in vitro activation or allogeneic stimulation. Itraconazole was administered to mice with GVHD and the effects in vivo were assessed. Results Itraconazole treatment decreased type 1 helper (Th1) and Th17 cells during in vitro T cell activation and allogeneic stimulation. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD. Conclusions In this study, we show that itraconazole ameliorates GVHD and is associated with reduced phosphorylated STAT3 (pSTAT3) levels and decreased Th17 cell differentiation. Therefore, itraconazole may have potential to ameliorate GVHD and tissue damage.