Abstract
BackgroundAbatacept, a CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and thus displays beneficial effects in the treatment of rheumatoid arthritis (RA). Although some studies have disclosed the in vitro effects of this biological agent on the immune-competent cells, the precise mechanisms of action in RA still remain unclear. The current studies were therefore undertaken to explore the effects of abatacept on monocytes in detail.MethodsMonocytes from healthy donors were cultured in the presence of staphylococcal enterotoxin B (SEB) with pharmacologically attainable concentrations of abatacept or control IgG-Fc. The expression of CD80 and CD86 and the induction of apoptosis of monocytes were measured by flow cytometry. The expression of CD80 and CD86 messenger RNA (mRNA) was determined by quantitative RT-PCR.ResultsAbatacept promoted apoptosis of SEB-stimulated monocytes. The induction of apoptosis of monocytes by these biological agents was reversed by the addition of IgG, but not IgG-F(ab′)2 fragments. Furthermore, abatacept significantly suppressed the expression of CD80, but not that of CD86 at protein levels. Finally, abatacept significantly suppressed the expression of mRNA for CD80 of monocytes stimulated with SEB, but not that of CD86.ConclusionsThese results demonstrate that one of the mechanisms of action of abatacept involves the induction of apoptosis of monocytes, which involves interaction with Fc receptor on monocytes. Moreover, the data also demonstrate that abatacept selectively suppresses the expression of CD80 at mRNA levels.
Highlights
Abatacept, a CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and displays beneficial effects in the treatment of rheumatoid arthritis (RA)
It was previously disclosed that etanercept was able to induce apoptosis of TNF-α expressing Jurkat T cells only in the presence of human Peripheral blood mononuclear cell (PBMC), whereas infliximab was able to induce their apoptosis through outside to inside signal via TNF-α in the absence of PBMCs [5]
It is possible that interactions with Fc receptors on monocytes might be required for the induction of apoptosis of monocytes by these biological agents
Summary
A CTLA4-Ig fusion protein attenuates T cell activation by inhibiting the CD80/86-CD28 costimulatory pathway that is required for the proper T cell activation and displays beneficial effects in the treatment of rheumatoid arthritis (RA). The current studies were undertaken to explore the effects of abatacept on monocytes in detail. A CTLA4-Ig fusion protein, attenuates T cell activation by inhibiting the CD80/CD86–CD28 costimulatory pathway that is required for the proper T cell activation and displays beneficial effects in the treatment of rheumatoid arthritis (RA) [1]. CTLA4-Ig has been suggested to display some effects other than inhibition of T cells. Reverse signaling to dendritic cells upon binding of CTLA4-Ig to CD80/ CD86 has been shown to interfere with dendritic cell activation and function [2, 3]. The current studies were undertaken to explore the effects
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