Predicting Organ Rejection After Transplant
Researchers at California Pacific Medical Center and Stanford University discover new means to predict patients at risk of organ rejection after transplant
October 14, 2013 (San Francisco, CA)
For the first time, physicians may be able to predict organ rejection in patients who have received a transplant for liver, kidney, heart or lung disease, and develop novel drugs for improving transplant outcomes.
The advancement in transplant medicine arises by way of new research from California Pacific Medical Center Research Institute (CPMCRI) and the Stanford University School of Medicine, in collaboration with colleagues in Belgium.
“We identified a set of 11 genes implicated in the immune response underlying acute organ rejection after solid organ transplantation, and these key genes can be manipulated to discover new drugs for treating transplant patients at a fraction of the current cost needed for pharmaceutical drug design,” said Minnie Sarwal (MD, PhD), co-senior author of the study and a Senior Scientist at CPMCRI. The other senior author is Atul Butte (MD, PhD), an Associate Professor of pediatrics at Stanford and Director of the Center for Pediatric Bioinformatics at Lucile Packard Children’s Hospital at Stanford.
The study of gene expression data was published online today in the Journal of Experimental Medicine.
Transplantation is an effective treatment for patients with severe kidney, heart, lung or liver disease. However, the risks of surgery include transplant rejection—where the recipient’s immune system recognizes the donor organ as foreign and attempts to remove or destroy it—and a series of immune responses that damage the transplanted organ over time, most often developing in kidney transplant patients.
“Our discovery sheds light on this cascade of immunogenic events underlying acute organ rejection, and will help physicians predict transplant failure and tissue damage in solid organ transplant, and monitor patients during their recovery after transplant,” said Dr. Sarwal.
She and colleagues analyzed the genes of 1164 biopsy samples from publically available tissue samples of patients at 11 hospitals across six countries, who had undergone transplantation of the heart, lung, kidney, or liver. They identified genes that had a high correlation with organ rejection, regardless of tissue type.
“Despite heterogeneity of data collected from different hospitals in different countries, the common rejection pathway that we identified is a critical axis of gene regulation driving acute rejection and graft injury following transplant, irrespective of the transplanted organ,” said Purvesh Khatri (PhD), lead author of the study and acting Assistant Professor of medicine at Stanford.
“We hypothesized that pharmacological disruption of the axis—drugs that target genes in this pathway—may reduce the immune response and increase graft survival, thus significantly promoting the chance of transplant success.”
Five of the 11 genes were found to be direct or indirect targets of FDA-approved drugs—meaning, drugs approved for their safety in other illnesses. Some of these medications may help lessen the immune response post-transplant (reducing the risk of organ rejection), and even promote graft survival. The researchers chose two of these drugs, atorvastatin and dasatinib, which are FDA-approved for non-transplant conditions.
The two drugs were first tested in mice who had received heart transplants, to determine their effects on the immune response after transplant. Both were shown to significantly inhibit immune cell activity after the heart transplants. To validate these findings, the researchers examined electronic medical records (EMRs) of more than 2500 kidney transplant patients, who were treated with statins for hypercholesterolemia. Their analysis of EMRs showed that patients who had received statins had longer graft survival than those who did not.
“Our findings provide a rapid, cost-effective, and targeted approach to repositioning drugs with known human safety, for use in patients undergoing organ transplant,” said Dr. Sarwal.
She noted that follow-up to the present study will be conducted to find the optimal combination and dosage of these drugs before they may be considered adjunctive agents in treating organ transplant patients.
Each year in the U.S., 50,000 patients receive organ transplants for kidney, liver, lung, and cardiovascular diseases.
The study was funded by the National Cancer Institute
(grant R01CA138256), the Lucile Packard Foundation for Children’s Health, and the National Institute of General Medical Sciences (grant R01GM079719).
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California Pacific Medical Center
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