Propagation of ebv-driven lymphomatous transformation of peripheral blood b cells by immunomodulators and biologics used in the treatment of inflammatory bowel disease

Nina Levhar, Bella Ungar, Uri Kopylov, Ella Fudim, Miri Yavzori, Orit Picard, Ninette Amariglio, Yehuda Chowers, Yonat Shemer Avni, Ren Mao, Minhu Chen, Ziyin Ye, Rami Eliakim, Shomron Ben Horin

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Immunomodulators and anti tumor-necrosis-α antibodies (anti-TNFs) have been implicated in increased risk of Epstein Barr virus (EBV) driven B-cell lymphoproliferative disorders in inflammatory bowel disease (IBD) patients. However, the underlying mechanisms are poorly understood. Methods: An in-vitro model of lymphoblastoid cell line (LCL) was established by co-incubation of EBV-infected human peripheral blood mononuclear cells (PBMC) with Cyclosporin-A (CSA). After 4 weeks, the resultant LCLs were analyzed by flow cytometry, telomerase activity assay, and next generation sequencing. Subsequently, LCLs were explored in the presence of therapeutic agents for IBD (anti-TNFs, vedolizumab, 6-Mercaptopurine [6MP], methotrexate). Epstein Barr virus titers were quantitated by real-Time polymerase chain reaction. Results: In cultures of PBMC with EBV and CSA, LCLs were characterized as an expanded, long lived population of CD58+CD23hi B-cells with high telomerase activity and clonal expansion. Upon addition to the cell cultures, LCL percentages were higher with infliximab (median 19.21%, P = 0.011), adalimumab (median 19.85%, P = 0.003), and early washed-out 6MP (median 30.57%, P = 0.043) compared with PBMC with EBV alone (median 9.61%). However, vedolizumab had no such effect (median 8.97%; P = 0.435). Additionally, LCL expansion was accompanied by increase in intracellular, rather than extracellular, EBV viral copies. Compared with PBMC with EBV alone, high levels of LCL were subsequently observed after triple depletion of NK cells, CD4+ T cells, and CD8+ T cells (median 52.8% vs 16.4%; P = 0.046) but also in cultures depleted solely of CD4+ T cells (median 30.7%, P = 0.046). Conclusions: These results suggest that both anti-TNFs and 6MP, but not vedolizumab, propagate EBV-driven lymphoblastoid transformation in an in vitro model of lymphoma. This model may prove useful for studying mechanisms underlying proneoplastic viral immune interactions of novel drugs in IBD therapy.

Original languageEnglish
Pages (from-to)1330-1339
Number of pages10
JournalInflammatory Bowel Diseases
Volume26
Issue number9
DOIs
StatePublished - 1 Sep 2020

Keywords

  • Epstein Barr virus
  • biological therapies
  • inflammatory bowel disease
  • lymphoblastoid cell line

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