title: Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation.
abstract: Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.
authors: Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Sameer
authors: S
authors: Lapsia
authors: Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Siva
authors: S
authors: Koganti
authors: Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Salvatore
authors: S
authors: Spadaro
authors: Division of Gastroenterology, Department of Internal Medicine, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Ramona
authors: R
authors: Rajapakse
authors: Division of Gastroenterology, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.
authors: Anupama
authors: A
authors: Chawla
authors: Division of Infectious Diseases, Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, New York.|Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York.
authors: Sumita
authors: S
authors: Bhaduri-McIntosh
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000150:complications* / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha
keywords: Epstein-Barr virus; anti-TNFα; inflammatory bowel disease; lymphomas; lytic activation