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