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OP0272 Abatacept is highly effective in inhibiting T cell priming but fails to induce T cell tolerance after primary antigen encounter
  1. A. Patakas1,
  2. S.G. Nadler2,
  3. J.M. Brewer1,
  4. I.B. McInnes1,
  5. P. Garside1
  1. 1Institute of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom
  2. 2Department of Immunology and Inflammation, Bristol Myers Squibb Co. Research and Development, Princeton, United States


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.

  1. 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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