CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis - Immunologie-Immunopathologie-Immunothérapie Access content directly
Journal Articles Circulation Research Year : 2023

CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis

Paul Régnier
Alexandre Le Joncour
  • Function : Author
Anna Maciejewski-Duval
  • Function : Author
Guillaume Darrasse-Jèze
Charles Dolladille
Wouter C Meijers
  • Function : Author
Lisa Bastarache
  • Function : Author
Pierre Fouret
  • Function : Author
Patrick Bruneval
  • Function : Author
Floriane Arbaretaz
Célia Sayetta
  • Function : Author
Ana Márquez
  • Function : Author
David Klatzmann
Patrice Cacoub
Javid J Moslehi
Joe-Elie Salem
David Saadoun

Abstract

BACKGROUND: Giant cell arteritis (GCA) causes severe inflammation of the aorta and its branches and is characterized by intense effector T-cell infiltration. The roles that immune checkpoints play in the pathogenesis of GCA are still unclear. Our aim was to study the immune checkpoint interplay in GCA. METHODS: First, we used VigiBase, the World Health Organization international pharmacovigilance database, to evaluate the relationship between GCA occurrence and immune checkpoint inhibitors treatments. We then further dissected the role of immune checkpoint inhibitors in the pathogenesis of GCA, using immunohistochemistry, immunofluorescence, transcriptomics, and flow cytometry on peripheral blood mononuclear cells and aortic tissues of GCA patients and appropriated controls. RESULTS: Using VigiBase, we identified GCA as a significant immune-related adverse event associated with anti-CTLA-4 (cytotoxic T-lymphocyte–associated protein-4) but not anti-PD-1 (anti-programmed death-1) nor anti-PD-L1 (anti-programmed death-ligand 1) treatment. We further dissected a critical role for the CTLA-4 pathway in GCA by identification of the dysregulation of CTLA-4–derived gene pathways and proteins in CD4 + (cluster of differentiation 4) T cells (and specifically regulatory T cells) present in blood and aorta of GCA patients versus controls. While regulatory T cells were less abundant and activated/suppressive in blood and aorta of GCA versus controls, they still specifically upregulated CTLA-4. Activated and proliferating CTLA-4 + Ki-67 + regulatory T cells from GCA were more sensitive to anti-CTLA-4 (ipilimumab)–mediated in vitro depletion versus controls. CONCLUSIONS: We highlighted the instrumental role of CTLA-4 immune checkpoint in GCA, which provides a strong rationale for targeting this pathway.
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Dates and versions

hal-04289514 , version 1 (16-11-2023)

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Paul Régnier, Alexandre Le Joncour, Anna Maciejewski-Duval, Guillaume Darrasse-Jèze, Charles Dolladille, et al.. CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis. Circulation Research, 2023, 133 (4), pp.298-312. ⟨10.1161/circresaha.122.322330⟩. ⟨hal-04289514⟩
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