Understanding Chronic Blood Vessel Inflammation in Arteritis

Cornelia Weyand, M.D

Emory University School of Medicine

Funded in January, 2002: $ for 0 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Understanding Chronic Blood Vessel Inflammation in Arteritis

Giant cell arteritis is an inflammatory disease of the blood vessel wall that can cause irreversible blindness and stroke. Prior research has shown that inflammation occurs after T cells become intolerant to cells in the blood vessel wall, resulting in vascular injury. The initial site of immune attack by T cells always contains an indigenous population of immature dendritic cells (DCs). Weyand has been a pioneer in identifying these DCs in the walls of blood vessels from humans and in analyzing their function by transplanting biopsies of blood vessels into mice.

Normally, DCs identify foreign cells and teach T cells to recognize and attack them. But when DCs mistake the body's own cells as foreign and instruct T cells to attack them, an autoimmune or self-attack situation is created. The researchers hypothesize that activation of these indigenous immature DCs attracts T cells to the site and is a critical event in the breakdown of tissue tolerance and the initiation of vasculitis. Moreover, they hypothesize, retention of these DCs at the inflammatory site and recruitment of additional DCs that are circulating in the blood, attract more T cells to the site. This sustains the disease process and leads to disease chronicity.

The investigators will examine this hypothesis using a mouse model in which human temporal arterial tissue taken during a diagnostic biopsy has been introduced. They will determine whether, in these temporal arteries with fully established giant cell arteritis, they can deplete the substance that attracts the T cells to the site, and determine if this terminates the disease process. If this is the case, they will have established that activated DCs are critical not only for initiating disease, but also for perpetuating it. This could lead to therapeutic innovations that target DCs to stop this ongoing disease.

ABSTRACT

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Understanding Chronic Blood Vessel Inflammation in Arteritis

Giant cell arteritis is a granulomatous disease that unfolds in the wall layers of medium-sized and large arteries. The immune-mediated injury induces fast and concentric occlusion of the affected arteries leading to ischemic complications such as blindness, stroke and aortic arch syndrome. CD4 T cells have been identified as the key regulatory cells in the vasculitic lesions. They undergo in situ clonal expansion and orchestrate the function of tissue injurious macrophages through the release of interferon-γ. In search for the antigen-presenting cells sustaining T cell activation, we have recently found that dendritic cells participate in the disease process. They derive from a population of indigenous dendritic cells that are strategically localized at the media-adventitia border of normal medium sized arteries. The current project is focused on examining the hypothesis that activation of arterial DC is a key event in the breakdown of tissue tolerance and the initiation of vasculitis. We will also investigate whether recruitment of DC into established vasculitic lesions provides a mechanism of antigen-spreading and disease chronicity.

Under physiologic conditions, arterial DC are in a resting state. By implanting temporal arteries into SCID mice, we can activate the tissue residing DC and explore the functional consequences for T cell activation. Specifically, we will study whether adventitial DC can take up and present antigenic peptides to adoptively transferred CD4 T cell clones. In preliminary experiments, we have shown that activating adventitial DC with LPS is sufficient to initiate DC-T cell interaction in the vascular wall. In Specific Aim 2 we will determine whether DC activation, through triggering of Toll-like receptors, will initiate macrophage recruitment and the development of panarteritis. In these experiments we will monitor functional activity of macrophage populations and the response pattern of vascular resident cells involved in intimal hyperplasia. Finally, we will study the role of DC captured in the lesions in presenting antigens taken up locally or transported in from the circulation. Continuous import of antigens by DC would perpetuate the disease process and lead to antigen spreading. Deciphering the contribution of tissue DC in GCA will further our knowledge on pathogenic principles in inflammatory blood vessels diseases, including the immunopathways operational in atherosclerotic coronary artery disease.

INVESTIGATOR BIOGRAPHIES

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Cornelia Weyand, M.D

Cornelia M. Weyand, M.D., obtained her medical and residency training in Germany, and took a fellowship in rheumatology at Stanford University. She then went to the University of Heidelberg in Germany where she completed a rheumatology fellowship, became a consultant in internal medicine, and then chief of the Division of Rheumatology there. She went to the Mayo Clinic in Rochester, Minnesota, in 1990 as an Assistant Professor of Immunology, became Associate Professor of Immunology and Medicine in 1993, and then Professor of Medicine in 1998 and a Professor of Immunology a year later. In 2000, she was appointed to a named Professorship of Medicine and Immunology, and in 2002 was appointed Director of the Clinical Immunology and Immunotherapeutics Program.

At the Mayo Clinic Dr. Weyand established a research team that investigated the role of the immune system in chronic inflammatory diseases. She was named the Barbara Woodward Lips Professor of Medicine and Immunology in 2000 and thereafter established and codirected the Clinical Immunology and Immunotherapeutics Program. Dr. Weyand came to the Emory University School of Medicine in 2004 as Professor of Medicine and Codirector of the Kathleen B. and Mason I. Lowance Center for Immunology. She is the recipient of several major awards for her rheumatology research.

FINDINGS

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Scientific Results:
The project has investigated innate and adaptive immune responses in medium and large vessel vasculitis. Giant cell arteritis, a granulomatous vasculitis, has served as a disease model. The progress made in this project, however, has had far-reaching implications, not only for vasculitides, but also on evolving concepts of inflammation in atherosclerosis.

Due to the vital function of blood vessels and their nonregenerative nature, vascular inflammation poses an immediate threat to the host, particularly when targeting large arteries. In giant cell arteritis, inflammatory destruction leads to blindness, stroke, and aortic aneurysm.  In the case of atherosclerotic disease, the inflammation is more localized, but inflammatory destruction of the atherosclerotic plaque causes myocardial infarction and stroke. The ultimate goal of this project was to understand how inflammation in human arteries is initiated and regulated. A critical element of this study was the discovery of dendritic cells (DC) that are indigenous to human arteries and function as gatekeepers in protecting arteries from immune attack.

In summary, studies supported by the project have been crucial in deciphering the immunoregulatory function of human arteries. The work has established that human blood vessels have sensing function for microbial infection. Exposure to pathogen-derived ligands initiates activation of adventitia-positioned DCs that are located closely to the vasa vasorum tree and obviously screen for circulating indicators of danger. Ligands for several Toll-like receptors (TLRs), including TLR3, TLR4, and TLR5, can all induce vascular DC activation. Remarkably, each ligand initiates a distinct DC activation program, and the instructions for T cells are unique for each of the stimulating patterns. Depending on the precise instruction provided by the vascular DC, T cells display tissue-invasive character or are arrested in the outer layer of the vessel wall. TLR4 stimulation emerges as a signal that most closely mimics conditions of vasculitis, raising the intriguing question of whether TLR4-binding molecules have a direct role in causing giant cell arteritis.

SELECTED PUBLICATIONS

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Mazlumzadeh M., Hunder G.G., Easley K.A., Calamia K.T., Matteson E.L., Griffing W.L., Younge B.R., Weyand C.M., and Goronzy J.J.   Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebo-controlled, randomized prospective clinical trial.   Arthritis Rheum. 2006 Oct;54(10):3310-8