Nse, providing a more cost effective means of introducing novel drugs for treatment of acute rejection in organ transplant recipients. The role of IL17 in innate and adaptive auto- and allo-immune responses has been investigated by several groups, but is still not fully understood. Clearly, IL17 was increased in human acute lung, liver and kidney rejection [4,34,35] and promoted early graft inflammation [36]. Results in experimental mouse models of cardiac AR reported that in Th1 transcription factor T-bet deficient mice, an IL17 response was mounted leading to acute graft rejection [2,5]. In another study IL17 was also involved in the acceleration of AR in a T-bet positive background with a full Th1 response [8]. The role of T-bet for IL17 mediated acute rejection remains controversial, yet most recent evidence suggests, that IL17 plays an accelerated role in a Th1 response suppressed environment [2]. Our results for IL17 Fruquintinib price expression in grafts from transplanted mice treated with Cys which majorly affects the Th1 response showed higher IL17 expression compared to nottreatment, whereas IFN-y was significantly lower. As current immunosuppressive drugs used in transplantation majorly act via the Th1 response, a potential increased emergence of IL17 in redundant acute rejection seems to be likely, and our microarray analyses provides further evidence for the role of IL17 pathway as an important mechanism of escape in more aggressive acute allograft rejection in patients on standard immunosuppression where IL17 MedChemExpress BIBS39 appears to drive the intensity of allograft inflammation. Thus synergistic inhibition of Th1 and IL17 pathways couldbe very promising and has been suggested by others [5]. On the contrary, Huh et al. found that cardiac glycosides inhibited differentiation of Th17 cells in vitro with high specificity by binding to the transcription factor RORyt [37]. This did not only result in a decreased IL17 transcription and production, but the isolate inhibition of RORyt by cardiac glycosides additionally resulted in reciprocal increased T-cell IFN-y and FOXP3 expression. The results by Huh et al further support our findings that a synergistic inhibition of both IFN-y and IL17 pathways as seen with Fenofibrate may be especially relevant in diseases where both immune axes play a significant role such as in acute allograft rejection. Despite this evidence, IL17 inhibitors are not currently used in transplantation and in the absence of any available synthetic IL17 inhibitors, we thus pursued the approach of drug repositioning Fenofibrate, a commercially available FDA approved drug, used for treatment of hyperlipidemia, and inferred from our study, to simultaneously inhibit the IL17 pathway and the Th1 mediated IFN-c pathway in acute graft rejection. Although Fenofibrate has never been used in transplantation, several studies including the FIELD study [11], indicated general anti-inflammatory pleiotropic effects in patients who were treated with Fenofibrate. In addition to Fenofibrate, steroids currently used in the post-transplant management of AR, were noted to also regulate many of the input AR genes in our dataset, supporting the reliability of our approach, though it is important to note that steroids did not regulate IL17. As Fenofibrate had been shown to inhibit expression of both the IL17 and the Th1 response gene IFN-c [10], Fenofibrate represented a very promising candidate for repositioning in transplantation. Thus, we characterized the anti.Nse, providing a more cost effective means of introducing novel drugs for treatment of acute rejection in organ transplant recipients. The role of IL17 in innate and adaptive auto- and allo-immune responses has been investigated by several groups, but is still not fully understood. Clearly, IL17 was increased in human acute lung, liver and kidney rejection [4,34,35] and promoted early graft inflammation [36]. Results in experimental mouse models of cardiac AR reported that in Th1 transcription factor T-bet deficient mice, an IL17 response was mounted leading to acute graft rejection [2,5]. In another study IL17 was also involved in the acceleration of AR in a T-bet positive background with a full Th1 response [8]. The role of T-bet for IL17 mediated acute rejection remains controversial, yet most recent evidence suggests, that IL17 plays an accelerated role in a Th1 response suppressed environment [2]. Our results for IL17 expression in grafts from transplanted mice treated with Cys which majorly affects the Th1 response showed higher IL17 expression compared to nottreatment, whereas IFN-y was significantly lower. As current immunosuppressive drugs used in transplantation majorly act via the Th1 response, a potential increased emergence of IL17 in redundant acute rejection seems to be likely, and our microarray analyses provides further evidence for the role of IL17 pathway as an important mechanism of escape in more aggressive acute allograft rejection in patients on standard immunosuppression where IL17 appears to drive the intensity of allograft inflammation. Thus synergistic inhibition of Th1 and IL17 pathways couldbe very promising and has been suggested by others [5]. On the contrary, Huh et al. found that cardiac glycosides inhibited differentiation of Th17 cells in vitro with high specificity by binding to the transcription factor RORyt [37]. This did not only result in a decreased IL17 transcription and production, but the isolate inhibition of RORyt by cardiac glycosides additionally resulted in reciprocal increased T-cell IFN-y and FOXP3 expression. The results by Huh et al further support our findings that a synergistic inhibition of both IFN-y and IL17 pathways as seen with Fenofibrate may be especially relevant in diseases where both immune axes play a significant role such as in acute allograft rejection. Despite this evidence, IL17 inhibitors are not currently used in transplantation and in the absence of any available synthetic IL17 inhibitors, we thus pursued the approach of drug repositioning Fenofibrate, a commercially available FDA approved drug, used for treatment of hyperlipidemia, and inferred from our study, to simultaneously inhibit the IL17 pathway and the Th1 mediated IFN-c pathway in acute graft rejection. Although Fenofibrate has never been used in transplantation, several studies including the FIELD study [11], indicated general anti-inflammatory pleiotropic effects in patients who were treated with Fenofibrate. In addition to Fenofibrate, steroids currently used in the post-transplant management of AR, were noted to also regulate many of the input AR genes in our dataset, supporting the reliability of our approach, though it is important to note that steroids did not regulate IL17. As Fenofibrate had been shown to inhibit expression of both the IL17 and the Th1 response gene IFN-c [10], Fenofibrate represented a very promising candidate for repositioning in transplantation. Thus, we characterized the anti.