To ensure long term allograft function and reduce non-tolerable side effects, novel immunosuppressive drugs are needed in Transplantation. In a novel bioinformatics driven drug discovery approach we investigated, whether already FDA approved drugs existed that target biologically relevant pathways which are redundant in transplant rejection despite immunosuppression. We performed quantitative microarray gene set analyses (GSA) using 3307 publicly available and manually created biologically functional gene-sets in 33 pre-transplant donor biopsies (D0) and matched 33 post renal transplant protocol biopsies with increasing grades of AR (no significant abnormalities STA, n=16; borderline AR, ARIA, ARIB, n=17). Identified rejection specific pathways were interrogated against a compound database of 7200 compounds to identify FDA approved drugs that interacted with the pathway input genes (existing PubMed entry). A selected FDA approved drug was tested in-vitro in PBMC and subsequently in-vivo in a murine cardiac AR model for its potential to attenuate AR and prolong graft survival.

The IL17 pathway was significantly enriched in patients with increasing grades of AR (GSA; FDR< 5%, D0>STA>BL>ARIA>ARIB). IL17 genes segregated patients into AR and STA and reflected AR subset segregation. Target-drug alignment studies identified Fenofibrate (FF) currently approved for hypertriglyceridemia to also target IL17. In antigen stimulated PBMC, FF down regulated IL17 expression as well as IFNG, TNF, IL1B, IL6. This was confirmed in vivo in allografts from cardiac transplanted mice treated with FF for 7 days. In the same mice, FF reduced graft infiltrating CD4+, CD8+ T-cells, as well as neutrophils, DC, NK and macrophages after 7 days of post-transplant treatment compared to non-treated animals (NT) (FACS, n=6 mice/group). Most importantly, FF significantly prolonged allograft survival by 11.5 days over NT (p=0.007; n=10 mice/group).

This study represents a novel approach for the identification of alternative drug targets opening the window for novel treatment options in transplantation.

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