Dendritic Cell Function in Inflammatory Diseases of Blood Vessels

Cornelia Weyand, M.D., Ph.D.

Emory University

Funded in December, 2002: $200000 for 5 years
LAY SUMMARY . ABSTRACT . 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 stroke and irreversible blindness.  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 on-going disease.

ABSTRACT

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Dendritic Cell Function in Inflammatory Diseases of Blood Vessels

Activation of DCs indigenous to the arterial adventitia is a critical event in the breakdown of tissue tolerance and the initiation of vasculitis.  Retention of site-activated and recruitment of circulating DCs sustains the disease process by maintaining a self-perpetuating lymphoid microstructure.  Recruitment of antigen-loaded DCs into a CCL19- and CCL21- rich extra-lymphoid lesion induces antigen spreading and disease chronicity.

Positioning of DCs in the adventitial layer of arteries indicates active surveillance of the vessel wall by the immune system.  Given the vital function of arteries and the potentially disastrous consequences of perivascular inflammation, it is highly likely that the physiologic function of adventitial DCs lies in the prevention of immune responses.  We have preliminary evidence that activation of adventitial DCs is sufficient to break tissue tolerance and is a key event in the pathogenesis of vasculitis. 

We have established an experimental model of GCA in which we can examine immune function in vivo.  The model uses human temporal arteries (TAs) obtained during diagnostic biopsy to generate human tissue-SCID mouse chimeras.  In this model, we can activate indigenous DCs residing in normal arteries and can trigger them to be immunogenetic for adoptively transferred CD4+ T cells.  In TAs with fully established GCA, depletion of CD83+ DCs terminates the disease process, demonstrating that activated DCs are critical antigen-presenting cells not only for disease initiation but also in established disease.  Thus, therapeutic interventions targeting DCs could be highly effective in GCA. 

To mechanistically examine our hypothesis we propose the following specific aims:
1. Investigate whether activation of adventitial DCs can initiate antigen-specific T-cell responses in the arterial wall.
2. Examine whether breakdown of tissue tolerance in the adventitia induces panarteritis, damages the tunica media, and initiates the response-to-injury program of the artery.
3. Examine antigen-presentation by DCs in GCA and compare two pathways of antigen provision, homing of circulating antigen-loaded DCs to the tissue and phagocytosis of antigen by tissue-resident DCs.

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 DC that are located closely to the vasa vasorum tree and obviously screen for circulating indicators of danger. Ligands for several Toll-like receptors (TLR), 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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Pryshchep O., Ma-Krupa W., Younge B.R., Goronzy J.J., and Weyand C.M.   Vessel-specific Toll-like receptor profiles in human medium and large arteries.   Circulation. 2008 Sep 16;118(12):1276-84.

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.

Weyand C.M., Ma-Krupa W., Pryshchep O., Gröschel S., Bernardino R., and Goronzy J.J.   Vascular dendritic cells in giant cell arteritis.   Ann N Y Acad Sci. 2005 Dec;1062:195-208.

Ma-Krupa W., Jeon M.S., Spoerl S., Tedder T.F., Goronzy J.J., and Weyand C.M.   Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis.   J Exp Med. 2004 Jan 19;199(2):173-83.

Weyand C.M., Ma-Krupa W., and Goronzy J.J.  Immunopathways in giant cell arteritis and polymyalgia rheumatica.  Autoimmun Rev. 2004 Jan;3(1):46-53.