title: A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.
abstract: Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.
authors.affiliation: Department of Pediatrics; 2 Stanford Cardiovascular Institute; 3 Department of Cardiothoracic Surgery; 4 Stanford Center for Biomedical Informatics Research, Department of Medicine; and 5 Institute for Immunity, Transplant, and Infection; Stanford University, Stanford, CA 94305.
authors.forename: Purvesh
authors.initials: P
authors.lastname: Khatri
authors.forename: Silke
authors.initials: S
authors.lastname: Roedder
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Katrien
authors.initials: K
authors.lastname: De Vusser
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Morgan
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Gong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fischbein
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Maarten
authors.initials: M
authors.lastname: Naesens
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D064591:Allografts; D000818:Animals; D000069059:Atorvastatin; D001706:Biopsy; D015331:Cohort Studies; D000069439:Dasatinib; D019992:Databases as Topic; D004195:Disease Models, Animal; D017277:Drug Approval; D057286:Electronic Health Records; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics*; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D016027:Heart Transplantation; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D016030:Kidney Transplantation; D015201:Meta-Analysis as Topic; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014180:Transplantation / Q000379:methods*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D006538:Heptanoic Acids; D011743:Pyrimidines; D011758:Pyrroles; D013844:Thiazoles; D000069059:Atorvastatin; D000069439:Dasatinib