Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells

• Published in: Atherosclerosis Vol. 220; no. 2; pp. 329 - 336
• Main Authors: Dietrich, Thore, Hucko, Thomas, Schneemann, Christiane, Neumann, Marleen, Menrad, Andreas, Willuda, Joerg, Atrott, Kirstin, Stibenz, Dietger, Fleck, Eckart, Graf, Kristof, Menssen, Hans D
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01-02-2012; Elsevier
• Subjects: Animals; Aorta - drug effects; Aorta - immunology; Aorta - metabolism; Aorta - pathology; Aortic Diseases - genetics; Aortic Diseases - immunology; Aortic Diseases - metabolism; Aortic Diseases - pathology; Aortic Diseases - prevention & control; apoE −/− mice; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - immunology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Cardiology. Vascular system; Cardiovascular; Cardiovascular Agents - administration & dosage; Cell Proliferation - drug effects; Diet, High-Fat; Disease Models, Animal; Extracellular matrix; Extradomain B fibronectin; Fundamental and applied biological sciences. Psychology; Humans; Injections, Intravenous; L19-IL2; Lipids - blood; Macrophages - drug effects; Macrophages - immunology; Magnetic Resonance Imaging; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Recombinant Fusion Proteins - administration & dosage; T-lymphocytes; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Time Factors; Vertebrates: cardiovascular system; Extracellular matrix; L19-IL2; T-lymphocytes; Extradomain B fibronectin; apoE −/− mice; Atherosclerosis; Rodentia; apoE―/― mice; Cardiovascular disease; Fibronectin; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; T-Lymphocyte
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.09.050

Abstract 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 pre-established 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.