Infliximab Induces Clonal Expansion of γδ-T Cells in Crohn’s Disease: A Predictor of Lymphoma Risk?

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Background: Concominant with the widespread use of combined immunotherapy in the management of Crohn’s disease (CD), the incidence of hepato-splenic gamma-delta (cd)-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 cd-T cell clones. We hypothesised that repeated infusion of anti-TNF-a agents may induce clonal selection and that concurrent treatment with immunomodulators further predisposes patients to cd-T cell expansion.

Methodology/Principal Findings: We investigated dynamic changes in the cd-T cells of patient with CD following treatment with infliximab (RemicadeH; n = 20) or adalimumab (HumiraH; n = 26) using flow cytometry. In patients with a high cd-T cell level, the cd-T cells were assessed for clonality. Of these 46 CD patients, 35 had a cd-T cells level (mean 1.6%) comparable to healthy individuals (mean 2.2%), and 11 CD patients (24%) exhibited an increased level of cd-T cells (5–15%). In the 18 patients also receiving thiopurines or methotrexate, the average baseline cd-T cell level was 4.4%. In three male CD
patients with a high baseline value, the cd-T cell population increased dramatically following infliximab therapy. A fourth male patient also on infliximab monotherapy presented with 20% cd-T cells, which increased to 25% shortly after treatment and was 36% between infusions. Clonality studies revealed an oligoclonal cd-T cell pattern with dominant cd-T cell clones.
In support of our clinical findings, in vitro experiments showed a dose-dependent proliferative effect of anti-TNF-a agents on cd-T cells.
Conclusion/Significance: CD patients treated with immunomodulators had constitutively high levels of cd-T cells. Infliximab exacerbated clonal cd-T cell expansion in vivo and induced cd-T cell proliferation in vitro. Overall, young, male CD patients with high baseline cd-T cell levels may be at an increased risk of developing malignant cd-T cell lymphomas following treatment with anti-TNF-a agents.
Original languageEnglish
JournalP L o S One
Volume6
Issue3
Pages (from-to)e17890
Number of pages9
ISSN1932-6203
DOIs
Publication statusPublished - 31 Mar 2011

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