Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0039483 (giant cell arteritis)
 3,204 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immature dendritic cells (DCs) are scattered throughout peripheral tissues and act as sentinels that sample the antigenic environment. After activation, they modify their chemokine receptor profile and migrate toward lymphoid tissues. On arrival, they have matured into chemokine-producing DCs that express co-stimulatory molecules and can prime naive T cells. Normal temporal arteries contain immature DCs that are located at the media-adventitia border. In temporal arteries affected by giant cell arteritis, DCs are highly enriched and activated and have matured into fully differentiated cells producing the chemokines, CCL18, CCL19, and CCL21. In keeping with their advanced maturation, DCs in the granulomatous lesions possess the chemokine receptor, CCR7. CCR7 binds CCL19 and CCL21, causing the highly activated DCs to be trapped in the peripheral tissue site. The co-stimulatory molecule, CD86, which is critical for DC/T-cell interaction, is expressed by a subset of DCs captured in the arterial wall. DC/T-cell interaction does not involve interleukin-12; transcripts for interleukin-12 p40 are absent in the vasculitic infiltrates. We propose that differentiation of DCs and the autocrine and paracrine actions of chemokines in granulomatous lesions misdirect DCs away from their usual journey to lymphoid organs and are critical in maintaining T-cell activation and granuloma formation in giant cell arteritis.
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PMID:Trapping of misdirected dendritic cells in the granulomatous lesions of giant cell arteritis. 1241 28

Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.
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PMID:Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2483 38