Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?

<h4>Background</h4>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 b...

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Autores principales:	Jens Kelsen, Anders Dige, Heinrich Schwindt, Francesco D'Amore, Finn S Pedersen, Jørgen Agnholt, Lisbet A Christensen, Jens F Dahlerup, Christian L Hvas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9513996591934d85848070cc69d43a23
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spelling	oai:doaj.org-article:9513996591934d85848070cc69d43a232021-11-18T06:56:23ZInfliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?1932-620310.1371/journal.pone.0017890https://doaj.org/article/9513996591934d85848070cc69d43a232011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21483853/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusion/significance</h4>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.Jens KelsenAnders DigeHeinrich SchwindtFrancesco D'AmoreFinn S PedersenJørgen AgnholtLisbet A ChristensenJens F DahlerupChristian L HvasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e17890 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jens Kelsen Anders Dige Heinrich Schwindt Francesco D'Amore Finn S Pedersen Jørgen Agnholt Lisbet A Christensen Jens F Dahlerup Christian L Hvas Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusion/significance</h4>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.
format	article
author	Jens Kelsen Anders Dige Heinrich Schwindt Francesco D'Amore Finn S Pedersen Jørgen Agnholt Lisbet A Christensen Jens F Dahlerup Christian L Hvas
author_facet	Jens Kelsen Anders Dige Heinrich Schwindt Francesco D'Amore Finn S Pedersen Jørgen Agnholt Lisbet A Christensen Jens F Dahlerup Christian L Hvas
author_sort	Jens Kelsen
title	Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
title_short	Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
title_full	Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
title_fullStr	Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
title_full_unstemmed	Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?
title_sort	infliximab induces clonal expansion of γδ-t cells in crohn's disease: a predictor of lymphoma risk?
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/9513996591934d85848070cc69d43a23
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Infliximab induces clonal expansion of γδ-T cells in Crohn's disease: a predictor of lymphoma risk?

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