Abatacept inhibits T cell priming by inducing of a unique transcriptional profile that reduces their ability to activate antigen presenting cells

Patakas, A., Ji, R., Weir, W. , Connolly, S. E., Benson, R. A., Nadler, S. G., Brewer, J. M. , McInnes, I. B. and Garside, P. (2016) Abatacept inhibits T cell priming by inducing of a unique transcriptional profile that reduces their ability to activate antigen presenting cells. Arthritis and Rheumatology, 68(3), pp. 627-638. (doi:10.1002/art.39470) (PMID:26473409)

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Abstract

Objectives: The objective of this study was to determine at the phenotypic, functional and transcriptional level whether abatacept, a CTLA-4Ig molecule that binds with high affinity to CD80/86 on antigen presenting cells and is used to treat rheumatoid arthritis, induces a state of immunological tolerance in T cells and dendritic cells. Methods: We investigated the capacity of abatacept to regulate the development of antigen-specific immunological tolerance in vivo using murine models of priming and tolerance to generate highly purified antigen specific T cell populations and CD11c+ antigen presenting cells. These were combined with detailed immunological and full genome transcriptional analysis. Results: We demonstrate that abatacept inhibits T cell activation, but does not render T cells anergic or lead to the generation of regulatory T cells. However, it induces 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 a 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 antigen presenting cells, with significant implications for its clinical application. This article is protected by copyright. All rights reserved.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Patakas, Dr Agapitos and Ji, Dr Ruirui and Benson, Dr Robert and Garside, Professor Paul and Brewer, Professor James and Weir, Dr William
Authors: Patakas, A., Ji, R., Weir, W., Connolly, S. E., Benson, R. A., Nadler, S. G., Brewer, J. M., McInnes, I. B., and Garside, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Science and Engineering > School of Engineering
Journal Name:Arthritis and Rheumatology
Publisher:Wiley
ISSN:0004-3591
ISSN (Online):2326-5205
Published Online:24 February 2016

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