$5 million to study immune responses to cancer-causing viruses in immunocompromised children

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Frequently Asked Questions for Organ Transplant Recipients

Matt Miller

Vikas Dharnidharka, MD, Alexis F. Hartmann Sr., MD, Distinguished Professor of Pediatrics, is the principal investigator on a National Cancer Institute grant to study the immune response to Epstein-Barr virus after organ transplantation in children.

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 study immune responses to cancer-causing viruses after organ transplantation in children.

Donated organs are a life-saving gift, but they can bring an unwelcome passenger – Epstein-Barr virus (EBV). Members of this family of herpes viruses are widespread and most people become infected in early adulthood, making EBV-negative donors extremely rare. Recipients may even become infected with the virus before transplantation. As with the chickenpox virus, a small viral reservoir persists after infection, hidden from the immune system—that is, until immunosuppression aimed at preventing organ rejection allows the virus to remain or reactivate while evading Immunoassays.

Among other illnesses, the virus causes mononucleosis, which is known on college campuses as the “kissing disease” because it is often spread through saliva. Healthy college students can usually make a full recovery with rest. Infected children may not develop symptoms. But in susceptible children who are immunocompromised after transplantation, the virus can also cause certain cancers, including non-Hodgkin lymphoma and Hodgkin’s disease. This post-transplant lymphoproliferative disorder is a group of disorders defined by the uncontrolled production of abnormal white blood cells that increases the risk of death after an organ transplant.

“It’s a double whammy,” said lead researcher Vikas Dharnidharka, MD, Alexis F. Hartmann Sr., MD, Distinguished Professor of Pediatrics. “We are transplanting organs infected with cancer-causing viruses while suppressing the recipient’s immune system. Preventing cancer requires immune surveillance, but preventing organ rejection requires immunosuppressants. If we understand how the immune system responds (or does not respond) to viruses, Maybe we can predict which children will develop cancer and prevent it.”

Other principal investigators at the University of Washington include: Kristine Wylie, PhD, assistant professor of pediatrics; Todd A. Fehniger, MD, PhD, professor of medicine; and Ken Schechtman, PhD, professor of biostatistics. Diana Meters, MD, professor of surgery and immunology at the University of Pittsburgh, is also a member of the multidisciplinary team.

Epstein-Barr viral load (or number of viruses) in the blood does not predict cancer susceptibility. To see whether children’s immune systems can reveal clues that predict susceptibility, the researchers plan to recruit 350 patients and collect five blood samples from each patient in the first year after organ transplantation. The medical school was one of three sites recruiting patients into the study. The other hospitals are Cincinnati Children’s Hospital Medical Center and Texas Children’s Hospital in Houston.

Researchers will study white blood cells called T cells during the first year after transplantation, comparing children with high and low EBV loads. Metes’ research shows that T cells in pediatric heart transplant recipients are exhausted or dysfunctional. These cells arise during chronic infection or cancer but fail to function optimally; the researchers wondered whether they would see the same dysfunction in enrolled patients who received all types of organs. They will examine about 60 markers to study cell identity.

The researchers also plan to study natural killer (NK) cells, white blood cells that destroy cancer cells and play an important role in fighting viral infections. They will investigate whether NK cells are dysfunctional in children with high EBV loads.

But exploring the immune system for answers is costly. Another project under the grant will focus on screening for a family of viruses called anelloviruses that are growing exponentially in response to immunosuppressive drugs and may be a relatively easy and affordable approach for clinical practice.

“We also aimed to study whether ring viral load could predict which children were at risk for certain cancers after transplantation,” said Dharnidharka, who remembers his first patient who developed post-transplant lymphoproliferative disorder. While in pediatric nephrology fellowship at Boston Children’s Hospital, a transplant case changed his career.

“I naively thought we were doing something great for patients,” he said. “A kidney transplant should help them. Then one patient developed post-transplant lymphoproliferative disease.”

He had never heard of it before.

“I can’t believe how little people know about it,” Danidakar said. “Since then, I have been passionate about adding knowledge to the field. Until we understand what the problem is, we can’t find a therapeutic target. “I hope that in the future we will never hear about post-transplant lymphoproliferative disease again. “