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- Title
BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B cells.
- Authors
Zhang, Ting-ting; Cheng, Rene Yu-Hong; Ott, Andee R.; Dahl, Noelle P.; Suchland, Emmaline R.; Stoffers, Claire M.; Asher, Gregory D.; Hou, Deyin; Thouvenel, Christopher D.; Hill, Tyler F.; Rawlings, David J.; James, Richard G.
- Abstract
Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo–differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV+ peripheral blood–derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV+ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD. Editor's summary: Recipients of hematopoietic stem cell transplants and solid organ transplants are at risk of developing posttransplant lymphoproliferative disease (PTLD), which is sporadic and associated with Epstein-Barr virus (EBV). However, the exact cause of PTLD and reasons it is sporadic within EBV carriers have been difficult to discern because of limited preclinical models. Here, Zhang et al. found that human B cell populations with rare cells carrying latent EBV differentiated ex vivo and transplanted into immunodeficient mice were sufficient to cause PTLD-like disease. The authors further discerned that these transplanted EBV+ B cells required signaling through their B cell receptor to expand in vitro and in vivo, suggesting that inhibitors of BCR signaling, such as ibrutinib, could be used as a therapy for individuals with PTLD. —Courtney Malo
- Subjects
B cells; B cell receptors; LYMPHOPROLIFERATIVE disorders; HEMATOPOIETIC stem cells; CELL populations; MUSCLE tumors
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 742, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adh8846