title: Local delivery of IL-2 reduces atherosclerosis via expansion of regulatory T cells.
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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine-Cardiology, Deutsches Herzzentrum, Berlin, Germany. thore@dhzb.de
authors: Thore
authors: T
authors: Dietrich
authors: Thomas
authors: T
authors: Hucko
authors: Christiane
authors: C
authors: Schneemann
authors: Marleen
authors: M
authors: Neumann
authors: Andreas
authors: A
authors: Menrad
authors: Joerg
authors: J
authors: Willuda
authors: Kirstin
authors: K
authors: Atrott
authors: Dietger
authors: D
authors: Stibenz
authors: Eckart
authors: E
authors: Fleck
authors: Kristof
authors: K
authors: Graf
authors: Hans D
authors: HD
authors: Menssen
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D007275:Injections, Intravenous; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
chemical_list: D001057:Apolipoproteins E; D002317:Cardiovascular Agents; C554817:L19-IL2 immunocytokine; D008055:Lipids; D011993:Recombinant Fusion Proteins