Oct. 22, 2024 – Recent research from Seattle Children’s Research Institute’s Center for Immunity and Immunotherapies (CIIT) focuses on post-transplant lymphoproliferative disorder (PTLD), a potentially life-threatening complication following organ or bone marrow transplantation. The findings, which delve into how to detect PTLD earlier and the factors that trigger disease onset, were published in Science Translational Medicine.
The majority of PTLD cases are caused by the Epstein-Barr virus (EBV), a common virus infecting more than 90% of the world’s population. EBV targets the immune system’s B cells and can be asymptomatic or cause mononucleosis in children and young adults. Once a person is infected with EBV, the virus stays within a very small fraction of the body’s B cells for life. In a person with a healthy immune system, EBV in these rare B cells remains latent — essentially sleeping. If EBV becomes active in healthy people, it is rapidly controlled by immune system T cells that patrol the body and eliminate EBV active B cells.
After a transplant, patients receive immunosuppressive drugs to prevent their bodies from rejecting the transplanted organ or bone marrow. These drugs weaken the immune system, making it more difficult for the body to fight off infections, or to control active EBV. Most transplant recipients receive cells or organs from donors who have been previously infected with EBV. In some cases, the EBV in these B cells becomes active and those cells can cause PTLD because the patrolling T cells are blocked from controlling the virus due to the immunosuppressive drugs. However, the events that lead to EBV becoming active and the biomarkers that might predict this process remain poorly understood.
The incidence of EBV-associated PTLD is rising due to increased numbers of transplants, older donors and recipients, and more potent immunosuppressive drugs. Some patients with PTLD show few symptoms while others develop terminal cancers. Better predictive and preemptive approaches to prevent and limit the incidence of PTLD would improve clinical outcomes and overall prognosis for patients with PTLD.
“ Our research unearths a crucial role for B cell receptor signaling and IgM-expressing memory B cells in promoting post-transplant lymphoproliferative disease. We believe the findings have significant implications for both the diagnosis and treatment of this disease.”
Modeling Disease
PTLD has been difficult to study using human B cells due to a lack of suitable models to recreate the viral process. In this study, CIIT principal investigators Richard James, PhD (also an associate professor in the Departments of Pediatrics and Pharmacology at the University of Washington School of Medicine) and David Rawlings, MD (CIIT director and professor in the Departments of Pediatrics and Immunology at the University of Washington School of Medicine) and colleagues isolated B cells from healthy donors and found they could cause symptoms similar to PTLD when transferred into an immunodeficient small-animal model that did not also receive healthy T cells.
The researchers found the primary driver of the PTLD-like pathologies were memory B cells that specifically produced Immunoglobulin M (IgM) antibodies. In this PTLD model, expanded B cells from some previously EBV-infected donors expressed genes associated with changes in EBV latency, suggesting that latent EBV in these cells was “waking up.” They discovered that these EBV-positive B cells required signaling through their B cell receptor (BCR) — a protein on the surface of the cell that activates the cell to respond against infection — to expand and exhibit changes in EBV latency.
“Our research unearths a crucial role for B cell receptor signaling and IgM-expressing memory B cells in promoting post-transplant lymphoproliferative disease,” Dr. James said. “We believe the findings have significant implications for both the diagnosis and treatment of this disease.”
Detection and Prevention
Prior to development of PTLD in their small-animal model, the research team saw a sudden, large spike in the level of IgM in the bloodstream, propelled by an increase in numbers of IgM-secreting B cells.
“PTLD is easier to treat when found early,” Dr. James said. “We believe early disease detection is possible through antibody level monitoring post-transplant, and our findings suggest that IgM should be evaluated as a key biomarker.”
The researchers also had success in delaying the onset of PTLD in the immunodeficient small-animal model with a clinically available BCR inhibitor drug, ibrutinib. Their overall findings imply that ibrutinib therapy might delay or even prevent symptoms of PTLD in at-risk transplant patients.
Future research includes validating IgM as a predictive biomarker of the likelihood of PTLD in human transplant patients and further characterizing how BCR signaling interacts with EBV during PTLD.
James Lab members, including first author Tingting Zhang, Rene Cheng, PhD, Greg Asher and Tyler Hill, as well as Christopher Thouvenel and Noelle Dahl of the Rawlings Lab, contributed to the findings.
This work was supported in part by Seattle Children’s Research Institute’s Program for Cell and Gene Therapy, the Children’s Guild Association Endowed Chair in Pediatric Immunology, the Hansen Investigator in Pediatric Innovation Endowment and the National Institutes of Health.
— Colleen Steelquist