Vasculitic T Cells in Giant Cell Arteritis
Investigator: Cornelia M. Weyand, M.D.
Cornelia Weyland, MD
Location: Emory University, Atlanta, GA
Timeline: July 1, 2008 - June 30, 2010
Abstract
Giant cell arteritis is a granulomatous vasculitis with T cell-macrophage infiltrates attacking medium-sized and large arteries. Multiple lines of evidence assign a key disease-promoting role to T cells. GCA is an HLA class II-associated disease; clonally related T cells expand in distinct regions of affected arteries, T cell clones from vascular lesions respond to tissue antigens and depletion of T-cell instructing dendritic cells strongly suppresses vasculitis. However, mechanisms through which CD4 T cells promote vessel-damaging immune responses are poorly understood. This proposal is designed to discover T cell effector functions promoting vessel wall inflammation. We will use two experimental models which recapitulate vasculitic immune responses: SCID mouse chimeras engrafted with human arteries and bioengineered human macrovessels. Specific Aim 1 is based on preliminary data that GCA-affected arteries contain IL-17, a T cell cytokine recently discovered as a major driver of autoimmune disease. We will examine IL-17 production in vasculitic T cell clones from GCA patients and investigate whether TH17 cells (T cells committed to IL-17 production) drive vascular inflammation in the vasculitis models. Specific Aim 2 focuses on an alternate T effector function, T-cell mediated cytotoxicity. We will examine whether GCA patients possess CD4 T cells that kill vascular smooth muscle cells and will test how such cytolytic T cells affect inflammation in and integrity of the vessel wall. Finally, in Specific Aim 3 we will search for novel GCA-relevant T effector pathways. We will apply gene expression profiling analyzing vascular T cell infiltrates in bioartificial arteries to find pathways relevant in the disease-promoting functions of such T cells; e.g. wall infiltration, control of pro-inflammatory macrophages, involvement in maladaptive healing responses, etc. The ultimate goal of this project is to define T cell-dependent disease pathways that can be therapeutically targeted to improve management of this devastating vasculitic syndrome.
Lay Person Summary
Patients with giant cell arteritis/temporal arteritis (GCA) are threatened by vision loss, stroke and aortic aneurysm. Laboratory tests show intense inflammation; blood vessel biopsies reveal clusters of inflammatory cells in the walls of arteries. Such inflammatory clusters are composed of T lymphocytes and macrophages, cells of the immune system, which react to yet unknown instigators and attack vessel walls. T lymphocytes are highly sophisticated cells, equipped with a large array of receptors and the ability to release local hormone-like substances (called cytokines) to drive inflammation and tissue injury. Over the last decade T lymphocytes have emerged as key regulators causing GCA. However, little is known about how they facilitate blood vessel damage. This proposal is designed to find out how T lymphocytes communicate with other immune cells and cells of the arterial wall to promote disease. The experiments are made possible because we have generated two experimental models in which we can study blood vessel wall inflammation: we engraft human arteries into mice or we generate human arteries through bioengineering. First, we will examine whether vasculitis is caused by T lymphocytes specialized in producing IL-17, a cytokine recently implicated in driving autoimmune disease. We will then explore whether T lymphocytes in GCA patients can kill essential cells, in particular vascular smooth muscle cells that form the scaffold of the blood vessel. We already have preliminary data that such killer T cells are circulating in the blood of GCA patients. Finally, we will use state-of-the-art techniques to discover new pathways through which lymphocytes damage the blood vessel structure. These experiments involve gene expression profiling and sophisticated bioinformatics methods to identify pathways of interest.
The ultimate goal is to overcome our current limitations in treating GCA by opening new avenues for novel therapeutic and diagnostic approaches urgently needed for affected patients.