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Title: A Common Rejection Module (CRM) across Multiple Transplant Organs Identifies Novel Therapeutics for Treatment of Acute Rejection in Solid Organ Transplantation
Authors: Roedder, S
Khatri, P
Kimura, N
De Vusser, Katrien
Morgan, A
Gong, Y
Fischbein, M
Robbins, R
Naesens, Maarten
Butte, A
Sarwal, M
Issue Date: 2013
Publisher: Munksgaard International Publishers
Host Document: American Journal of Transplantation vol:13 pages:80-80
Conference: 13th American Transplant Congress (ATC) location:Seattle: WA date:MAY 18-22, 2013
Abstract: We performed meta-analyses of eight datasets comprising whole genome microarray expression profiles on 236 graft biopsy samples from four types of transplanted organs (kidney, lung, heart and liver). We identified a common rejection module (CRM) consisting of 11 genes (BASP1, CD6, CXCL10, CXCL9, INPP5D, ISG20, LCK, NKG7, PSMB9, RUNX3, and TAP1) that were significantly overexpressed (p<0.0005) during acute rejection, irrespective of the transplanted organ. After validating overexpression of these genes in four independent cohorts consisting of 525 human renal transplant biopsies, we predicted that two FDA-approved drugs (Atorvastatin and Dasatinib) approved for non-transplant indications, can reduce graft cell-infiltration and improve graft survival. We validated the prediction in a HLA-mismatched murine transplant model with significant reduction of graft infiltrating cells and extended graft survival after administration of Atorvastatin or Dasatinib. We further validated significantly increased graft survival in transplanted patients taking Atorvastatin in a retrospective analysis using electronic medical records from >2500 renal transplant patients, followed for up to 22 years. Based on these results, clinical validation of the repositioning of Atorvastatin and Dasatinib for extending allograft survival is warranted.
ISSN: 1600-6135
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Nephrology

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