Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice.
Nicole CaduffDonal McHughAnita MurerPatrick RämerAna RaykovaVanessa LandtwingLisa RiebleChristian W KellerMichael PrummerLaurent HoffmannJanice K P LamAlan Kwok Shing ChiangFriedrich RaulfTarik AzziChristoph BergerTina Rubic-SchneiderElisabetta TraggiaiJan D LünemannMichael KammüllerChristian MünzPublished in: PLoS pathogens (2020)
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.
Keyphrases
- epstein barr virus
- diffuse large b cell lymphoma
- gene expression
- stem cells
- high fat diet induced
- type diabetes
- chronic kidney disease
- newly diagnosed
- end stage renal disease
- metabolic syndrome
- genome wide
- adipose tissue
- signaling pathway
- mesenchymal stem cells
- oxidative stress
- dna methylation
- risk factors
- skeletal muscle
- replacement therapy
- prognostic factors
- diabetic rats