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CTLA-4 Pathway Is Instrumental in Giant Cell Arteritis.

• アブストラクト	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.
  ジャーナル名	Circulation research
  投稿日	2023/7/12
  投稿者	Regnier, Paul; Le Joncour, Alexandre; Maciejewski-Duval, Anna; Darrasse-Jeze, Guillaume; Dolladille, Charles; Meijers, Wouter C; Bastarache, Lisa; Fouret, Pierre; Bruneval, Patrick; Arbaretaz, Floriane; Sayetta, Celia; Marquez, Ana; Rosenzwajg, Michelle; Klatzmann, David; Cacoub, Patrice; Moslehi, Javid J; Salem, Joe-Elie; Saadoun, David
  組織名	Immunology-Immunopathology-Immunotherapy (i3) Laboratory, INSERM UMR-S 959,;Sorbonne Universite, Paris, France (P.R., A.L.J., A.M.-D., G.D.-J., M.R., D.K.,;P.C., D.S.), Assistance Publique-Hopitaux de Paris (AP-HP), France.;Biotherapy Unit (CIC-BTi), Inflammation-Immunopathology-Biotherapy Department;(DHU i2B), Groupe Hospitalier Pitie-Salpetriere (P.R., A.L.J., A.M.-D., M.R.,;D.K., P.C., D.S.), Assistance Publique-Hopitaux de Paris (AP-HP), France.;Departement de Medecine Interne et Immunologie Clinique, Sorbonne Universite,;AP-HP, Groupe Hospitalier Pitie-Salpetriere, Paris, France (A.L.J., P.C., D.S.).;Centre National de Reference Maladies Autoimmunes Systemiques Rares, Centre;National de Reference Maladies Autoinflammatoires et Amylose Inflammatoire,;Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), Paris, France;(A.L.J., P.C., D.S.).;Faculte de Medecine Paris Descartes (G.D.-J.), Universite de Paris, France.;Normandie University, University of Caen Normandy, Centre Hospitalier;Universitaire (CHU) de Caen Normandie, PICARO Cardio-Oncology Program, Department;of Pharmacology, INSERM ANTICIPE U1086: Unite de Recherche Interdisciplinaire;pour la Prevention et le Traitement des Cancers, Centre Francois Baclesse, France;(C.D.).;Department of Cardiology, University Medical Center Groningen, University of;Groningen, the Netherlands (W.C.M., J.-E.S.).;Department of Biomedical Informatics, Vanderbilt University Medical Center,;Nashville, TN (L.B.).;Service d'anatomie et cytologie pathologiques, Groupe Hospitalier;Pitie-Salpetriere (P.F.), Assistance Publique-Hopitaux de Paris (AP-HP), France.;Service d'anatomie pathologie, Hopital Europeen Georges Pompidou (P.B.),;Assistance Publique-Hopitaux de Paris (AP-HP), France.;Centre d'Histologie, d'Imagerie et de Cytometrie, Centre de Recherche des;Cordeliers, Sorbonne Universite, INSERM (F.A.), Universite de Paris, France.;ICM Institut du Cerveau, CNRS UMR7225, INSERM U1127, Sorbonne Universite, Hopital;de la Pitie-Salpetriere, Paris, France (C.S.).;Instituto de Parasitologia y Biomedicina "Lopez-Neyra," CSIC, PTS Granada, Spain;(A.M.).;Systemic Autoimmune Disease Unit, Instituto de Investigacion Biosanitaria de;Granada, Spain (A.M.).;Section of Cardio-Oncology and Immunology, Division of Cardiology and the;Cardiovascular Research Institute, University of California San Francisco;(J.J.M.).;Department of Pharmacology, INSERM, CIC-1901, UNICO-GRECO Cardiooncology Program,;Sorbonne Universite (J.-E.S.), Assistance Publique-Hopitaux de Paris (AP-HP),;France.
  Pubmed リンク	https://www.ncbi.nlm.nih.gov/pubmed/37435729/

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