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Updated: May 6, 2026
A Standardized Murine Model with a Three-Person Workflow for Studying Acute Cellular and Antibody-Mediated Rejection in Xenotransplantation
Published on: March 20, 2026
A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ
Purvesh Khatri1, Silke Roedder, Naoyuki Kimura
1Department 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.
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.
Insights
Researchers discovered a common gene module (CRM) that accurately diagnoses acute rejection (AR) across organ transplants. This discovery offers new diagnostic tools and identifies existing drugs like atorvastatin for potential AR treatment, improving graft survival.
Area of Science:
- Transplantation immunology
- Genomics
- Drug discovery
Background:
- Acute rejection (AR) is a major challenge in organ transplantation, impacting graft survival.
- Accurate and early diagnosis of AR is crucial for timely intervention.
- Identifying common molecular signatures across different organ transplants can lead to broader diagnostic and therapeutic strategies.
Purpose of the Study:
- To identify a common molecular signature associated with acute rejection across multiple organ transplants.
- To evaluate the diagnostic and prognostic capabilities of this signature.
- To explore the potential of existing drugs for repurposing in managing acute rejection.
Main Methods:
- Meta-analysis of eight independent transplant gene expression datasets (236 samples).
- Validation of identified gene module in three independent cohorts (794 samples).
- Correlation analysis with graft injury and prediction of future injury in renal transplant biopsies (151 samples).
- In silico drug mechanism inference and in vivo validation in mouse cardiac transplant models.
- Retrospective analysis of electronic medical records (2,515 renal transplant patients).
Main Results:
- Identified an 11-gene common rejection module (CRM) significantly overexpressed in AR across four organs.
- CRM demonstrated high specificity and sensitivity for diagnosing AR in independent cohorts.
- CRM gene expression correlated with graft injury extent and predicted future injury.
- Atorvastatin and dasatinib modulated CRM genes, reduced infiltrating cells, and extended graft survival in mice.
- Atorvastatin showed a beneficial effect on long-term graft survival in a large patient cohort.
Conclusions:
- A common rejection module (CRM) serves as a robust biomarker for acute rejection across diverse organ transplants.
- The CRM offers significant potential for improved AR diagnosis and monitoring.
- FDA-approved drugs, atorvastatin and dasatinib, show promise for repurposing to treat acute rejection, warranting further clinical investigation.
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