Researchers at Washington University School of Medicine in St. Louis have received a $5.7 million grant from the National Cancer Institute of the National Institutes of Health (NIH) to investigate immune responses to a cancer-causing virus after organ transplantation in children.
A donated organ is a lifesaving gift, but it can come with an unwanted passenger - the Epstein-Barr virus (EBV). This member of the herpes virus family is widespread and infects most people by early adulthood, making EBV-negative donors extremely rare. Recipients may even contract the virus before transplantation. Like the chickenpox virus, a small viral reservoir persists after infection, hidden from the immune system - that is, until the immunosuppression aimed at preventing organ rejection allows the virus to take hold or reactivate while escaping immune detection.
Among other ailments, the virus causes mononucleosis, an illness dubbed the "kissing disease" across college campuses, as it commonly spreads through saliva. Healthy college students typically fully recover with rest. Infected children may not experience symptoms. But in vulnerable post-transplant immunocompromised children, the virus also can cause certain cancers, including non-Hodgkin lymphoma and Hodgkin disease. Such post-transplant lymphoproliferative disorders, a group of conditions defined by the uncontrolled production of abnormal white blood cells, heighten the risk of death after organ transplantation.
"It is a double hit," said lead principal investigator Vikas Dharnidharka, MD, the Alexis F. Hartmann Sr., MD, Endowed Professor of Pediatrics. "We are transplanting organs infected with a cancer-causing virus while dampening the recipient's immune system. Immune surveillance is needed to prevent the cancer, but immunosuppressants are needed to prevent organ rejection. If we understand how the immune system is responding - or not - to the virus, maybe we can predict which children will develop cancer and prevent it from occurring."
The other Washington University principal investigators on the grant are: Kristine Wylie, PhD, an assistant professor of pediatrics; Todd A. Fehniger, MD, PhD, a professor of medicine; and Ken Schechtman, PhD, a professor of biostatistics. Diana Metes, MD, a professor of surgery and immunology at the University of Pittsburgh, is also part of the multidisciplinary team.
Epstein-Barr viral load - or the amount of virus - in the blood does not predict cancer susceptibility. To see if the children's immune systems can reveal clues to what does predict susceptibility, the researchers aim to enroll 350 patients and collect five blood samples per patient in the first year after organ transplantation. The School of Medicine is one of three sites enrolling patients in this study. The others are the Cincinnati Children's Hospital Medical Center and Texas Children's Hospital in Houston.
The researchers will investigate white blood cells called T cells during the first year after transplantation, comparing children with high to low EBV loads. Work by Metes has shown exhausted or dysfunctional T cells in pediatric heart transplant recipients. These cells arise during chronic infection or cancer but don't function optimally; the researchers wonder if they will see the same dysfunction in the enrolled patients receiving all types of organs. They will look at roughly 60 markers to investigate cellular identities.
The researchers also plan to study natural killer (NK) cells, the white blood cells that destroy cancer cells and are important in fighting viral infections. They will investigate whether NK cells are dysfunctional in the children with high EBV loads.
But probing the immune system for answers is expensive. Another project that is part of the grant will focus on screening for a family of viruses, the Anelloviruses, which increases exponentially under immunosuppressive drugs, and may be a relatively easy and affordable method to put into clinical practice.
"We also aim to study whether Anellovirus loads can predict which children are at risk of developing certain cancers after transplantation," said Dharnidharka, who remembers his first patient who developed a post-transplant lymphoproliferative disorder. A single transplantation case during his pediatric nephrology fellowship at Boston Children's Hospital changed his career.
"I was naive in thinking that we were doing something great for our patients," he said. "The kidney transplant was supposed to help them. And then a patient developed a post-transplant lymphoproliferative disorder."
He had never heard of it before.
"I couldn't believe how little was known about it," Dharnidharka said. "It has since become my passion to add knowledge to the field. Until we understand what is going wrong, we can't find therapeutic targets. I hope for a future in which post-transplant lymphoproliferative disorders are never heard of again."
The grant award is awarded by the National Cancer Institute of the National Institutes of Health (NIH), grant number U01CA275304-01A1.
About Washington University School of Medicine
WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children's hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.
