Pitt receives $14.5 million from NIH to improve pediatric heart transplantation outcomes

02/13/04

Children's Hospital of Pittsburgh transplant physician Steven Webber to lead effort

PITTSBURGH, Feb. 13 The University of Pittsburgh has been awarded an estimated $14.5 million from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) to develop novel approaches that seek to improve the outcomes of pediatric heart transplant recipients. The five-year grant establishes the University of Pittsburgh as a Specialized Center of Clinically Oriented Research (SCCOR) in Pediatric Heart Development and Disease. Such a center encourages basic science research findings to be applied more rapidly to address specific clinical problems.

Steven A. Webber, MBChB, is principal investigator of the SCCOR grant, which entails three unique clinical projects and four resource cores that support the research. Dr. Webber is associate professor of pediatrics at the University of Pittsburgh School of Medicine and medical director of Heart and Heart/Lung Transplantation at Children's Hospital of Pittsburgh.

The grant has important clinical relevance because most children and infants who receive heart transplants have significantly shortened life expectancies. Immunosuppressive regimens, while offering significant improvements in short-term outcomes, have inherent risks that hinder long-term patient survival and quality of life. Negative effects include infections, cancerous growths and failure to prevent chronic rejection, the leading cause of death after heart transplantation. Nearly every patient faces bouts of acute rejection and some sort of immunosuppressive drug-related complication.

"Further improvements in clinical outcomes following pediatric heart transplantation depend on novel strategies that link basic science advances to modifications in clinical protocols," stated Dr. Webber. "We're poised to take these advances to the next level and apply them in the patient-care setting where we can best determine their promise," he added.

Each of the clinical research projects capitalizes on findings of basic science and preliminary clinical research performed by University of Pittsburgh and Children's Hospital researchers. These include results of studies of the role of the thymus in the development of transplant tolerance in children, the genetic contributions to differences in patient outcomes and how certain cells may aid in the immune response to prevent certain post-transplant tumors.

As such, the center grant brings together experts in pediatric cardiology and transplant medicine, transplant surgery, immunology, pharmacology, infectious diseases, molecular genetics and biostatistics from the University of Pittsburgh's School of Medicine, Graduate School of Public Health (GSPH) and Thomas E. Starzl Transplantation Institute as well as from Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center. In addition to Children's, six other leading transplant centers will be involved.

The three clinical studies to be conducted through the center are:

  • Continuation of a unique trial involving the inoculation of unmodified donor bone marrow into the thymus during heart transplantation. Dr. Webber is leading this project the only one of its kind that seeks to enhance graft acceptance in pediatric heart transplant patients. The ultimate goal of these kinds of studies is tolerance, or long-term graft acceptance without the need for immunosuppression, which is considered the Holy Grail of transplant medicine. Preliminary results in 14 patients who received thymic injections indicated significantly fewer "late" rejection episodes and less immunosuppression requirements one to five years after the procedure compared to 23 patients who did not receive donor bone marrow. Through the grant, these patients will continue to be followed and a second group of patients will be enrolled in a blinded, controlled trial.
  • Studies of Epstein-Barr virus (EBV) infection and immune response, culminating with a Phase I trial of a cellular immunotherapy for the prevention and treatment of post-transplant lymphoproliferative disease (PTLD). Because anti-rejection drugs heavily suppress the immune system, almost one in 10 pediatric heart transplant recipients will develop these tumors by seven years after transplantation. Most PTLD cases evolve from an EBV infection. David T. Rowe, Ph.D., associate professor of infectious diseases and microbiology at GSPH, is principal investigator of this project, which will track EBV viral loads and the behavior of the virus leading to PTLD. Diana Metes, M.D., research assistant professor of surgery and immunology, School of Medicine and Starzl Transplantation Institute, will study how the immune system allows the development of tumors to occur. Such studies will result in a trial of a therapy using a patient's own immune system T cells that will be activated to recognize and fight EBV. Conventional treatment of PTLD involves reducing immunosuppression until tumors shrink, but organ rejection can result and sudden death is a risk.
  • A multi-center study looking at multiple genetic markers that may be predictive of an individual's transplant outcome and help explain why African Americans do worse than other groups of patients. Such an approach would allow clinicians to individualize treatments, diminishing the chances of rejection and minimizing drug-related complications. Adriana Zeevi, Ph.D., professor of pathology and surgery at the School of Medicine and the Starzl Transplantation Institute, is principal investigator. The study will involve 750 pediatric heart transplant recipients from Children's Hospital of Pittsburgh, Loma Linda University, Washington University, Columbia University, Stanford University and the University of Alabama at Birmingham. Genetic studies will be performed at the University of Pittsburgh and the University of Southern California.

    Four cores will support the clinical projects. Dr. Webber will lead the Administrative Core. Dr. Metes will lead the Immunological Monitoring Core; Sheryl F. Kelsey, Ph.D., professor of epidemiology at GSPH, will lead the Biostatistics and Data Management Core; and Bradley B. Keller, M.D., professor of pediatrics at the School of Medicine and chief of cardiology at Children's, will head the Clinical Research Skills Development Core. This unique core will provide a structured training environment for talented future physician-scientists who aspire to careers in translational research.

    "The University of Pittsburgh is uniquely qualified to carry out the primary objective of NIH's new Specialized Centers for Clinically Oriented Research program. Our mission through the Schools of the Health Sciences and our partner, the University of Pittsburgh Medical Center, has always been to foster multidisciplinary collaborations and to promote the translation of basic science research into the clinical setting," said Arthur S. Levine, M.D., senior vice chancellor for the health sciences and dean of the School of Medicine at the University of Pittsburgh.

    "This SCCOR enables our talented researchers and clinicians to take aim at addressing the fundamental barriers to heart transplant success in children. The NHLBI is to be commended for recognizing the special problems of the pediatric population by funding this and other pediatric projects," added David H. Perlmutter, M.D., Vira I. Heinz Professor and chairman of the department of pediatrics at the University of Pittsburgh School of Medicine and physician-in-chief at Children's Hospital of Pittsburgh.

    Source: Eurekalert & others

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