期刊
ATHEROSCLEROSIS
卷 220, 期 2, 页码 329-336出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2011.09.050
关键词
Atherosclerosis; Extracellular matrix; Extradomain B fibronectin; T-lymphocytes; L19-IL2; apoE(-/-) mice
资金
- Bayer-Pharma AG
Objective: Recent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis. Methods and results: L19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE(-/-) mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of preestablished atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls (p < 0.01), whereas the macrophage marker Mac3 was significantly reduced (p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control (p < 0.03). Conclusion: L19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE(-/-) mice resulting in significant plaque size reduction mediated by local Tregs. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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