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

  • Caduff N University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • McHugh D University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Murer A University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Rämer P University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Raykova A University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Landtwing V University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Rieble L University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
  • Keller CW University Hospital of Münster, Department of Neurology with Institute of Translational Neurology, Münster, Germany.
  • Prummer M Nexus Personalized Health Technologies, ETH Zurich, Zurich Switzerland, and Swiss Institute for Bioinformatics (SIB), Zurich, Switzerland.
  • Hoffmann L Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Lam JKP Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong.
  • Chiang AKS Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong.
  • Raulf F Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Azzi T Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland.
  • Berger C Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland.
  • Rubic-Schneider T Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Traggiai E Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Lünemann JD University Hospital of Münster, Department of Neurology with Institute of Translational Neurology, Münster, Germany.
  • Kammüller M Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • Münz C University of Zurich, Viral Immunobiology, Institute of Experimental Immunology, Zurich, Switzerland.
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  • 2020-04-07
Published in:
  • PLoS pathogens. - 2020
Animals
B-Lymphocytes
DNA, Viral
Disease Models, Animal
Epstein-Barr Virus Infections
Female
Gene Expression Profiling
HLA-A2 Antigen
Herpesvirus 4, Human
Humans
Immunocompromised Host
Immunosuppressive Agents
Lymphoproliferative Disorders
Male
Mice
Mice, Inbred NOD
Mice, Transgenic
Organ Transplantation
Tacrolimus
Transcriptome
Viral Load
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/77882
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