Journal: PLoS ONE

Article Title: Significance and Suppression of Redundant IL17 Responses in Acute Allograft Rejection by Bioinformatics Based Drug Repositioning of Fenofibrate

doi: 10.1371/journal.pone.0056657

Figure Lengend Snippet: Whole genome microarrays from 66 pre- and post-transplant kidney graft biopsies and from 35 post-transplant kidney graft biopsies were analyzed for rejection specific injury pathways using 3 computational databases comprising 3305 independent gene-sets. AR specific IL17 pathway (FDR = 0.3, p = 0.011) and activated IL17 + T-helper cells cell (FDR = 0.5; p = 0.008) gene-sets were aligned to a database of 7200 compounds with proven interactions with the input genes (MetaCore™, GeneGo, Thomson Reuters) resulting in the identification of Fenofibrate for drug repositioning in AR. Efficacy of Fenofibrate was tested in vitro using human PBMC and in vivo in mouse total allo-mismatch cardiac rejection for anti-inflammatory and for its potency to prolong graft survival.

Article Snippet: AR specific IL17 pathway and IL17+ T-helper cell genes were interrogated against the MetaCore™ (GeneGo, St. Joseph, MI) Compound Database evaluating the interaction of rejection specific genes against data of 7200 different therapeutic and non-therapeutic compounds in the drug lookup interface.

Techniques: In Vitro, In Vivo

Journal: PLoS ONE

Article Title: Significance and Suppression of Redundant IL17 Responses in Acute Allograft Rejection by Bioinformatics Based Drug Repositioning of Fenofibrate

doi: 10.1371/journal.pone.0056657

Figure Lengend Snippet: PCR of RNA from mice cardiac allografts (5a) and recipient spleens (b) corroborated in vitro findings and further characterized the mechanism of Fenofibrate to regulate the IL17 pathway and Th1 response (c). Gene expression results in mice recipient grafts (a,c) and spleens (b,c) at POD7 are displayed as box and whisker plots of mean relative fold changes with 10 th and 90 th percentile to universal RNA after 18S normalization using the ΔΔCt method. Significance between Fenofibrate (FF) treatment over no treatment (NT) and between Cyclosporine (Cys) treatment over no treatment were calculated by a 2-sided Student t-test and a p-value of p<0.05 considered as significant. Results of our additional network analyses in MetaCore revealed a central role for the transcription factor c-jun (c). Subsequent PCR for c-jun and its associated cytokine receptor IL7R showed decreased expression by Fenofibrate and suggested different sites of actions in spleen and grafts (c).

Article Snippet: AR specific IL17 pathway and IL17+ T-helper cell genes were interrogated against the MetaCore™ (GeneGo, St. Joseph, MI) Compound Database evaluating the interaction of rejection specific genes against data of 7200 different therapeutic and non-therapeutic compounds in the drug lookup interface.

Techniques: In Vitro, Expressing, Whisker Assay