title: Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen-Presenting Cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: Agapitos
authors.initials: A
authors.lastname: Patakas
authors.affiliation: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey.
authors.forename: Rui-Ru
authors.initials: RR
authors.lastname: Ji
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: William
authors.initials: W
authors.lastname: Weir
authors.affiliation: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Connolly
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Benson
authors.affiliation: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Brewer
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.affiliation: University of Glasgow, College of Medical, Veterinary, and Life Sciences, Glasgow, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Garside
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D000941:Antigens / Q000276:immunology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D012313:RNA / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D046888:Tissue Array Analysis; D014158:Transcription, Genetic / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000941:Antigens; D018501:Antirheumatic Agents; D012313:RNA; D000069594:Abatacept