title: Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
abstract: BACKGROUND
  Concominant with the widespread use of combined immunotherapy in the management of Crohn's disease (CD), the incidence of hepato-splenic gamma-delta (γδ)-T cell lymphoma has increased sharply in CD patients. Malignant transformation of lymphocytes is believed to be a multistep process resulting in the selection of malignant γδ-T cell clones. We hypothesised that repeated infusion of anti-TNF-α agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to γδ-T cell expansion.
  
  
  RESULTS
  We investigated dynamic changes in the γδ-T cells of patient with CD following treatment with infliximab (Remicade®; n=20) or adalimumab (Humira®; n=26) using flow cytometry. In patients with a high γδ-T cell level, the γδ-T cells were assessed for clonality. Of these 46 CD patients, 35 had a γδ-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of γδ-T cells (5-15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline γδ-T cell level was 4.4%. In three male CD patients with a high baseline value, the γδ-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% γδ-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal γδ-T cell pattern with dominant γδ-T cell clones. In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-α agents on γδ-T cells.
  
  
  CONCLUSIONS
  CD patients treated with immunomodulators had constitutively high levels of γδ-T cells. Infliximab exacerbated clonal γδ-T cell expansion in vivo and induced γδ-T cell proliferation in vitro. Overall, young, male CD patients with high baseline γδ-T cell levels may be at an increased risk of developing malignant γδ-T cell lymphomas following treatment with anti-TNF-α agents.
authors.affiliation: Gastro-Immuno Research Laboratory (GIRL), Department of Medicine V, Aarhus University Hospital, and Institute of Molecular Biology, Aarhus University, Aarhus, Denmark. jenskels@rm.dk
authors.forename: Jens
authors.initials: J
authors.lastname: Kelsen
authors.forename: Anders
authors.initials: A
authors.lastname: Dige
authors.forename: Heinrich
authors.initials: H
authors.lastname: Schwindt
authors.forename: Francesco
authors.initials: F
authors.lastname: D'Amore
authors.forename: Finn S
authors.initials: FS
authors.lastname: Pedersen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Agnholt
authors.forename: Lisbet A
authors.initials: LA
authors.lastname: Christensen
authors.forename: Jens F
authors.initials: JF
authors.lastname: Dahlerup
authors.forename: Christian L
authors.initials: CL
authors.lastname: Hvas
mesh_terms: D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000069285:Infliximab; D008223:Lymphoma / Q000209:etiology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000069285:Infliximab