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.

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.

Keywords: Atherosclerosis, Extracellular matrix, Extradomain B fibronectin, T-lymphocytes, L19-IL2, apoE^−/− mice