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Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta

Nadkarni, S; Mauri, C; Ehrenstein, MR; (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J EXP MED , 204 (1) 33 - 39. 10.1084/jem.20061531. Green open access

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Abstract

The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4(+)CD25(hi) T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4(+)CD25(-) T cells. This defect, however, was overcome after anti-tumor necrosis factor (TNF)-alpha antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4(+)CD25(hi)FoxP3(+) T reg cell population, which mediates suppression via transforming growth factor (TGF)-beta and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L(-) T reg cells from CD4(+)CD25(-) T cells isolated from active RA patients, a process dependent on TGF-alpha. In spite of the potent suppressor capacity displayed by this CD62L(-) T reg cell population, the natural CD62L(+) T reg cells remained defective in infliximab-treated patients. These results suggest that anti-TNF-alpha therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance.

Type: Article
Title: Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta
Open access status: An open access version is available from UCL Discovery
DOI: 10.1084/jem.20061531
Publisher version: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC21184...
Keywords: TRANSCRIPTION FACTOR FOXP3, GROWTH-FACTOR-BETA, EXPRESSION, INDUCTION, COLITIS, PHENOTYPE, LINEAGE, SUBSET, IL-10, CURE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/6977
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