title: Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis.
abstract: BACKGROUND
  Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids.
  
  
  RESULTS
  Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses.
  
  
  CONCLUSIONS
  Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.
authors.affiliation: Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA.
authors.forename: Kisha
authors.initials: K
authors.lastname: Piggott
authors.forename: Jiusheng
authors.initials: J
authors.lastname: Deng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Warrington
authors.forename: Brian
authors.initials: B
authors.lastname: Younge
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Kubo
authors.forename: Manisha
authors.initials: M
authors.lastname: Desai
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D013700:Giant Cell Arteritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous
chemical_list: D002135:Calcium-Binding Proteins; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; C064045:delta protein; D007371:Interferon-gamma