Background Absence of co-stimulation (Signal 2) in the presence of TCR-stimulation (Signal-1) has been linked to the induction of tolerance, deletion or anergy. Abatacept is a CTLA-4-Ig molecule that binds with high affinity to CD80/86 on antigen presenting cells. It modulates CD28-mediated T cell co-stimulation and is currently used to treat rheumatoid arthritis, however it is unknown if its use leads to the development of immunological tolerance.
Objectives To gain a greater understanding of the mode of action of Abatacept by investigating in vivo its ability to induce antigen-specific immunological tolerance.
Methods We employed TcR transgenic mice, oral tolerance and adoptive transfer systems1 to investigate whether abatacept can induce a state of immunological tolerance during primary antigen encounter.
Results We demonstrate that while abatacept treatment significantly modulates antigen specific T cell priming in vivo, this condition does not replicate the phenotype and functional state of T cell tolerance. T cells tolerised by antigen feeding were unable to produce IL-2 after ex-vivo restimulation, in contrast T cells primed in the presence of abatacept produced copious amounts of this cytokine and resembled naïve T cells. Furthermore, T cells primed in the presence of abatacept were characterised by the absence of CD25+ FoxP3+, more resembling naïve than tolerised T cells. Compared with abatacept treatment, tolerised T cells exhibited a significantly higher proportion of CD25+ FoxP3+ T cells and expressed higher levels of inhibitory molecules, such as CTLA-4. However, while transgenic T cells in tolerised mice expressed an antigen-experienced phenotype (CD44highCD62L-), abatacept treatment significantly inhibited T cell activation, as demonstrated by the high proportion of CD44lowCD62L+ transgenic T cells in these mice. Moreover, upon secondary in vivo exposure to antigen, abatacept treated T cells expanded to the same degree as naïve or primed T cells and to a significantly greater extent than tolerised T cells.
Conclusions In this study we demonstrate that abatacept does not induce a state of immunological tolerance after primary antigen encounter, however it significantly inhibits T cell activation.
Rush CM, Millington OR, Hutchison S, Bryson K, Brewer JM, Garside P. Characterization of CD4+ T-cell–dendritic cell interactions during secondary antigen exposure in tolerance and priming. Immunology 2009;128(4):463-471.
Disclosure of Interest A. Patakas Grant/Research support from: This research was funded by BMS that has financial interest in Abatacept, S. Nadler: None Declared, J. Brewer: None Declared, I. McInnes: None Declared, P. Garside: None Declared
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