Large vessel vasculitides (LVV), such as giant cell arteritis (GCA) cause blindness, stroke, aortic arch syndrome, aortic aneurysm, hypertension and myocardial insufficiency. In an aging population the number of patients requiring chronic management for LVV has been steadily rising, while the therapeutic armamentarium has remained strictly limited to high-dose corticosteroids. The last decade has seen exciting progress in implicating the innate and adaptive immune system in the immunopathogenesis of LVV. However, there is a critical gap in our knowledge why the disease targets the aorta and its major branches and how immuno- stromal communications in the arterial wall initiate and promote vasculitis. The pathogenic immune response has a signature of antigen-induced clonal expansion, but we have recently seen that costimulatory signals deriving from resident cells in the tissue niche are equally important in driving tissue-damaging immunity. GCA arteries express abundant levels of NOTCH receptors and ligands, providing a molecular platform for superb cell-to-cell communication. Blocking of NOTCH signaling effectively inhibits vasculitis. CD4 T cells from GCA patients constitutively express NOTCH1 receptor, enabling them to interact with NOTCH ligand expressing vascular smooth muscle cells (VSMC) and endothelial cells (EC). This application is designed to uncover how the Notch pathway participates in immuno-endothelial and immuno-stromal communications and how NOTCH- dependent signaling shapes vasculitogenic T cell responses and maladaptive VSMC and EC behavior. The project builds on a series of enabling resources;including a clinically phenotyped cohort of GCA patients;a novel 3-D model system of human arterial walls which permits assembly of custom-made vessels from stackable units populated with defined cell populations;and a humanized mouse model carrying inflamed human arteries. Access to Notch receptor and ligands can be blocked through ligand-competing antibodies/fusion proteins and cells can be rendered Notch signaling deficient by RNAi technology.
Specific Aim 1 examines on a mechanistic level how NOTCH ligands on VSMC and EC regulate effector functions of vasculitogenic CD4 T cells;modulate their growth, tissue invasion capacity and cytokine production.
Specific Aim 2 seeks to identify signaling networks that can be utilized to either suppress NOTCH1 expression or target NOTCH-dependent survival signals in pathogenic T cells. Small molecule inhibitors disrupting Notch-derived signals will be tested in the chimera model for their anti-vasculitic potential.
Specific Aim 3 is focused on the role of VSMC as signal-sending and signal-receiving cells and determines how NOTCH-NOTCH ligand interactions affect VSMC survival, migration, matrix production, contractility and ROS release.
Specific Aim 4 unravels the molecular mechanisms through which patient-derived CD4+NOTCH1+ T cells regulate the functional behavior of ECs and investigates how such T cells modulate EC proinflammatory functions, angiogenic capacity, adhesiveness and leakiness of the EC barrier.

Public Health Relevance

Large vessel vasculitis (giant cell arteritis) is a life-threatening disease of the aorta and its major branches which causes aortic aneurysms as well as vascular occlusions. The disease is initiated by the immune system but the blood vessel itself contributes to vascular damage. Because current therapies are limited to high-dose corticosteroids, this project seeks to understand how immune cells communicate with blood vessel cells and how blocking such communications can be exploited for novel therapeutic approaches.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Mcdonald, Cheryl
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Zhang, Hui; Watanabe, Ryu; Berry, Gerald J et al. (2017) Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A 114:E970-E979
Wen, Zhenke; Shen, Yi; Berry, Gerald et al. (2017) The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Sci Transl Med 9:
Watanabe, Ryu; Shirai, Tsuyoshi; Namkoong, Hong et al. (2017) Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity. J Clin Invest 127:2725-2738
Shen, Yi; Wen, Zhenke; Li, Yinyin et al. (2017) Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol 18:1025-1034
Weyand, Cornelia M; Zeisbrich, Markus; Goronzy, Jörg J (2017) Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr Opin Immunol 46:112-120
Kim, C; Fang, F; Weyand, C M et al. (2017) The life cycle of a T cell after vaccination - where does immune ageing strike? Clin Exp Immunol 187:71-81
Goronzy, Jörg J; Weyand, Cornelia M (2017) Successful and Maladaptive T Cell Aging. Immunity 46:364-378
Uribe, Jorge A; Aggarwal, Ishita; Witthayaweerasak, Juthamat et al. (2017) Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis. J Neuroophthalmol :
Watanabe, Ryu; Hosgur, Ebru; Zhang, Hui et al. (2017) Pro-inflammatory and anti-inflammatory T cells in giant cell arteritis. Joint Bone Spine 84:421-426
Weyand, Cornelia M; Berry, Gerald J; Goronzy, Jörg J (2017) The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. J Leukoc Biol :

Showing the most recent 10 out of 74 publications