Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells. Issue 3 (March 2016)

• Record Type: Journal Article
• Authors: Patakas, Agapitos; Ji, Rui‐Ru; Weir, William; Connolly, Sean E.; Benson, Robert A.; Nadler, Steven G.; Brewer, James M.; McInnes, Iain B.; Garside, Paul
• Is Part Of: Arthritis & rheumatology. Volume 68:Issue 3(2016)
• Page Start: 627
• Page End: 638
• Publication Date: 2016-03
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.39470
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: To determine at the phenotypic, functional, and transcriptional levels whether abatacept, a CTLA‐4Ig molecule that binds with high affinity to CD80/86 on antigen‐presenting cells (APCs) and is used to treat rheumatoid arthritis, induces a state of immunologic tolerance in T cells and dendritic cells in mice. Methods: We investigated the capacity of abatacept to regulate the development of antigen‐specific immunologic tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen‐specific T cell populations and CD11c+ APCs. These were combined with detailed immunologic and full genome transcriptional analyses. Results: We found that abatacept inhibited T cell activation, but did not render T cells anergic or lead to the generation of Treg cells. However, it induced a sustained inhibition of T cell activation due to the inability of these cells to progress through the cell cycle following T cell receptor stimulation. We also observed that this state was accompanied by an inhibition of dendritic cell activation due to their reduced licensing by T cells. Conclusion: This study provides detailed insight into the mode of action of abatacept, demonstrating that its effectiveness is not due to the induction of T cell tolerance, but rather to a sustained inhibition of T cell activation that results in reduced functionality of APCs, with significant implications for its clinical application.