Journal Article

Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis

Michael Bonelli, Lisa Göschl, Stephan Blüml, Thomas Karonitsch, Kiyoshi Hirahara, Elisabeth Ferner, Carl-Walter Steiner, Günter Steiner, Josef S. Smolen and Clemens Scheinecker

in Rheumatology

Volume 55, issue 4, pages 710-720
Published in print April 2016 | ISSN: 1462-0324
Published online December 2015 | e-ISSN: 1462-0332 | DOI: http://dx.doi.org/10.1093/rheumatology/kev403
Abatacept (CTLA-4Ig) treatment reduces T cell apoptosis and regulatory T cell suppression in patients with rheumatoid arthritis

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Objective. Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients.

Methods. Phenotypic and functional analyses of CD4+ T cells, including CD4+ FoxP3+ CD25+ regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4+ and CD4+ FoxP3+ T cells was measured by TUNEL staining.

Results. We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4+ T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression.

Conclusion. CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment.

Keywords: abatacept; CTLA-4Ig; rheumatoid arthritis; regulatory T cells; Foxp3

Journal Article.  5526 words.  Illustrated.

Subjects: Rheumatology ; Pharmacology

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