Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-{alpha} therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-{beta}

Centre For Rheumatology, Department of Medicine, Windeyer Institute, University College London, London W1T 4JF, England, UK.
Journal of Experimental Medicine (Impact Factor: 13.91). 02/2007; 204(1):33-9. DOI: 10.1084/jem.20061531
Source: PubMed

ABSTRACT The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi 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- [corrected] 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+CD25hiFoxP3+ 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-beta. 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.

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Available from: Suchita Nadkarni, Aug 27, 2015
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    • "The analysis of Tregs in these particular settings is aimed at evaluating their possible function as marker of response to treatment as well as considering their role in the pathogenesis of these diseases and finally hypothesizing new therapeutic strategies that could involve the Treg pathway. Studies in rheumatoid arthritis (RA) have shown that infliximab (a chimeric anti-TNFí µí»¼) and methotrexate may lead to a significant rise in the number of peripheral blood Tregs in patients responding to this therapy [19] and induce in vitro the differentiation of a population of Tregs expressing FOXP3 through conversion of CD4 + CD25 − T cells [20]. "
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    • "What kind of factors impair the functions of Treg populations? Tumor necrosis factor- (TNF ) has been reported to contribute to dysfunction of Treg cells and consequent breakdown of immunological self-torelance in Rheumatoid Arthritis (RA) (Nadkarni et al., 2007). TNF- is one of main causative factors in RA, and anti-TNF treatment (infliximab etc) led to the elevated number of Treg cells and restored the partly impaired suppressive functions. "
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