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

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.

Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease

“…Further investigation will now be required to identify the microbial/host-derived signals that may drive this process, although these are likely to include increased intestinal permeability (17), changes in the composition of the microbiota (1,44), and systemic priming of innate leukocytes by bacterial products translocated from the gut (21). Indeed, it has already been reported that environmental exposures influence γδ T cell frequency in human peripheral blood (25) and that stable expansions of Vδ2 T cells can occur in the circulation of patients with IBD (45,46). Consistent with these data, Vδ2 T cells have also been identified in the gut in a small number of CD patients (13,14), although the role played by these cells in mucosal inflammation in CD has, until now, remained obscure.…”

“…Indeed, lymphoma risk in AZA-treated IBD has been reported to progressively increase with therapy duration (52), and older male patients are at the greatest risk of AZA-induced malignancy (53). Furthermore, HSTCL in AZA-treated CD is frequently of γδ T cell origin (49), and anti-TNF therapy reportedly increases the proliferation of γδ T cells in young, male CD patients (46). These data suggest that the Vδ2 T cell population itself may become dysregulated and eventually undergo malignant transformation in AZA-treated CD.…”

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

“…An example of this is seen in people with Crohn's disease who were found to have a global deficit in the number of cd T cells present. 98 Evidence that this may be a result of activation-induced cell death as opposed to an inherent immune anomaly of the disease comes from the observation that treatment with infliximab, an anti-TNFa agent, resulted in clonal expansion of cd T cells in Crohn's patients on treatment 105 , highlighting the potential in vivo role of TNFa signalling in cd T cell self-modulation. However, in vitro studies looking at the functional effects of infliximab on cd T cells derived from patients with Behçet's disease or rheumatoid arthritis, in contrast, found that the expansion and reactivity of these excitable T cells was notably impaired, 106,107 underscoring again the often discrepant outcomes when attempting to extrapolate findings from manipulated artificial settings in vitro to what occurs in vivo.…”

Gamma Delta T Cell Subset V Gamma 2+ Expansion Associated with Longterm Infliximab Treatment in a Patient with Ankylosing Spondylitis

“…Because TNF-α is inhibitory to Vδ2+ T cell proliferation 10 , it is possible that IFX has promoted the proliferation of these cells. Further work is required to elucidate such a mechanism.…”