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

Caduff, Nicole and McHugh, Donal and Murer, Anita and Rämer, Patrick and Raykova, Ana and Landtwing, Vanessa and Rieble, Lisa and Keller, Christian and Prummer, Michael and Hoffmann, Laurent and Lam, Janice and Chiang, Alan and Raulf, Friedrich and Azzi, Tarik and Berger, Christoph and Rubic-Schneider, Tina and Traggiai, Elisabetta and Lünemann, Jan and Kammueller, Michael and Münz, Christian (2020) Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice. PLoS pathogens, 16 (4). pp. 1-25. ISSN 15537374

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.

Item Type: Article
Date Deposited: 02 May 2020 09:48
Last Modified: 02 May 2020 09:48
URI: https://oak.novartis.com/id/eprint/38805

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