Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen-Presenting Cells

Autor: Rui-Ru Ji, Paul Garside, Steven G. Nadler, James M. Brewer, William Weir, Agapitos Patakas, Sean E. Connolly, Iain B. McInnes, Robert A. Benson
Rok vydání: 2016
Předmět:
Zdroj: Arthritis & Rheumatology. 68:627-638
ISSN: 2326-5191
Popis: 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.
Databáze: OpenAIRE
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