Study could help transplant surgeons predict rejection/tailor medications

Children's Hospital of Pittsburgh receives $1.1 million grant from NIH

PITTSBURGH Oct. 11, 2006 A Children's Hospital of Pittsburgh of UPMC transplant surgeon and researcher has received a grant from the National Institutes of Health to study genetic factors that could predispose transplant recipients to rejection.

The goal of the four-year, $1.1 million grant is to study these factors in order to predict before transplant which patients are more likely to experience rejection. This information may be used to tailor anti-rejection medications accordingly, according to Rakesh Sindhi, MD, co-director of Children's Hillman Center for Pediatric Transplantation and principal investigator of the study. He plans to enroll 80 children receiving liver transplants at Children's.

"Based on the results of this study, a patient more likely to reject a transplanted organ may someday receive high doses of anti-rejection medicine initially. Those who are less likely to reject could have lower doses, or less potent combinations," said Dr. Sindhi, an associate professor of surgery at the University of Pittsburgh School of Medicine. "By applying individualized anti-rejection strategies before the transplant even occurs, we hope to reduce rejection rates and drug-induced side effects for pediatric liver transplant from 50 percent to about 20 percent."

Surgical techniques have improved survival rates for pediatric organ transplantation dramatically over the last 25 years. As a result, the challenge has shifted to improving quality of life. Anti-rejection medications are important because, while they make transplantation possible, they also can have adverse side effects that can themselves become life-threatening, such as infections and cancers.

Researchers will study the multiple processes that cause rejection in blood cells. This information will be linked to the unique "genomic fingerprint" of a liver transplant candidate, based on the inheritance of more than 500,000 mutations from parent to child. These mutations, known as nucleotide polymorphisms, represent "misspellings" in the genetic code, are present in all people and form the basis of inherited predisposition to a variety of diseases and outcomes, according to Dr. Sindhi.

"There is evidence from our earlier research that these mutations can be transmitted from parent to child in certain patterns that indicate if a transplant candidate is predisposed to rejection, a rejection-free state or tolerance, a rare occurrence whereby anti-rejection medications no longer are required," he said. "Any tool that could help guide us in deciding when and by how much to lower anti-rejection medications would be invaluable in improving the quality of life for our patients."

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Dr. Sindhi's grant is from the National Institute of Allergy and Infectious Diseases. Grant collaborators include: the Genetics and Proteomics Laboratories at Pitt; the Department of Human Genetics at Pitt; Duke University; and the EMMES Corporation in Bethesda, Md.

For more information about Dr. Sindhi's research or the Hillman Center for Pediatric Transplantation at Children's, please visit www.chp.edu.


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