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

TitleImmunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice
Authors
Issue Date2020
PublisherPublic Library of Science. The Journal's web site is located at http://pathogens.plosjournals.org/perlserv/?request=index-html&issn=1553-7374
Citation
PLoS Pathogens, 2020, v. 16 n. 4, p. article no. e1008477 How to Cite?
AbstractPost-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.
Persistent Identifierhttp://hdl.handle.net/10722/289323
ISSN
2023 Impact Factor: 5.5
2023 SCImago Journal Rankings: 2.223
PubMed Central ID
ISI Accession Number ID
Errata

 

DC FieldValueLanguage
dc.contributor.authorCaduff, N-
dc.contributor.authorMcHugh, D-
dc.contributor.authorMurer, A-
dc.contributor.authorRämer, P-
dc.contributor.authorRaykova, A-
dc.contributor.authorLandtwing, V-
dc.contributor.authorRieble, L-
dc.contributor.authorKeller, CW-
dc.contributor.authorPrummer, M-
dc.contributor.authorHoffmann, L-
dc.contributor.authorLam, JKP-
dc.contributor.authorChiang, AKS-
dc.contributor.authorRaulf, F-
dc.contributor.authorAzzi, T-
dc.contributor.authorBerger, C-
dc.contributor.authorRubic-Schneider, T-
dc.contributor.authorTraggiai, E-
dc.contributor.authorLünemann, JD-
dc.contributor.authorKammüller, M-
dc.contributor.authorMünz, C-
dc.date.accessioned2020-10-22T08:11:01Z-
dc.date.available2020-10-22T08:11:01Z-
dc.date.issued2020-
dc.identifier.citationPLoS Pathogens, 2020, v. 16 n. 4, p. article no. e1008477-
dc.identifier.issn1553-7366-
dc.identifier.urihttp://hdl.handle.net/10722/289323-
dc.description.abstractPost-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.-
dc.languageeng-
dc.publisherPublic Library of Science. The Journal's web site is located at http://pathogens.plosjournals.org/perlserv/?request=index-html&issn=1553-7374-
dc.relation.ispartofPLoS Pathogens-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleImmunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice-
dc.typeArticle-
dc.identifier.emailChiang, AKS: chiangak@hku.hk-
dc.identifier.authorityChiang, AKS=rp00403-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.ppat.1008477-
dc.identifier.pmid32251475-
dc.identifier.pmcidPMC7162544-
dc.identifier.scopuseid_2-s2.0-85083620852-
dc.identifier.hkuros317481-
dc.identifier.volume16-
dc.identifier.issue4-
dc.identifier.spagearticle no. e1008477-
dc.identifier.epagearticle no. e1008477-
dc.identifier.isiWOS:000531365400044-
dc.publisher.placeUnited States-
dc.relation.erratumdoi:10.1371/journal.ppat.1009167-
dc.identifier.issnl1553-7366-

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