Abstract
BackgroundConcominant 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.Methodology/Principal FindingsWe 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.Conclusion/SignificanceCD 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.
Highlights
T cells that express the cd subunits of the T cell receptor link innate and adaptive immunity and have been implicated in the pathogenesis of autoimmune diseases, Crohn’s disease (CD) [1]
CD patients had a mean frequency of 1.6% cd-T cells of total CD3+ T cells, with values ranging from 1.3–2.0%
Despite several case reports detailing the development of Hepatosplenic T cell lymphoma (HSTCL) in CD patients, it has not been possible to determine if the anti-TNF-a agents played a primary role in the lymphomagenesis or if HSTCL should be regarded as the result of a clonal evolution within the more generalised chronic inflammatory processes that characterise inflammatory bowel disease (IBD)
Summary
T cells that express the cd subunits of the T cell receptor link innate and adaptive immunity and have been implicated in the pathogenesis of autoimmune diseases, Crohn’s disease (CD) [1]. Higher cd-T cell frequencies have been found in CD patients [2], and these increased levels have been reported to mirror disease activity, with higher levels in patients with active disease[3]. Approximately 200 cases of HSTCL have been reported worldwide Of these cases, 28 cases were reported in patients with inflammatory bowel disease (IBD). With the exception of one case, the occurrence of anti-TNF-a treatment–associated HSTCL has only been reported in IBD patients [5,8]. Of these 28 cases, 22 patients had received infliximab in combination with a thiopurine analogue (azathioprine or 6-mercaptopurine) [9], 3 cases were associated with the use of infliximab followed by adalimumab. 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
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