Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

Nicole Caduff, Donal McHugh, Anita Murer, Patrick Rämer, Ana Raykova, Vanessa Landtwing, Lisa Rieble, Christian W. Keller, Michael Prummer, Laurent Hoffmann, Janice K.P. Lam, Alan K.S. Chiang, Friedrich Raulf, Tarik Azzi, Christoph Berger, Tina Rubic-Schneider, Elisabetta Traggiai, Jan D. Lünemann, Michael Kammüller, Christian Münz

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferation-associated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies.

Original languageEnglish
Article numbere1008477
JournalPLoS Pathogens
Volume16
Issue number4
DOIs
StatePublished - 1 Apr 2020
Externally publishedYes

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