Abstract 18483: Therapeutic Administration of IL-2/ Anti-IL-2 Monoclonal Antibody Complexes Enhances Healing After Experimental Myocardial Infarction in Mice
Background: The role of innate immunity in healing and remodeling after myocardial infarction (MI) has been studied in great detail. Recently, we demonstrated that Foxp3+CD4+ regulatory T cells (Treg cells) facilitate wound healing post-MI. We therefore pursued a strategy to activate Treg cells in a therapeutic fashion by employing a treatment modality with clinical potential, i.e. by administration of interleukin (IL)-2/ anti-IL-2 monoclonal antibody (IL-2 mAB) complexes.
Methods and results: Mice were subjected to experimental MI and treated with IL-2/ IL-2 mAB complexes beginning on day 1 after infarction. IL-2 and anti-IL-2 mAB (clone JES5-1) were mixed at a molar ratio of 1:2 and each mouse was treated on three consecutive days receiving a dose of 6 μg IL-2/ IL-2 mAB complexes per injection corresponding to approximately 5000 IU IL-2 per day. Mice were monitored for up to 7 days. IL-2/ IL-2 mAB complex treatment attenuated left-ventricular remodeling by trend and preserved cardiac function compared to vehicle-treated control mice as evaluated by echocardiography 7 days after MI (6.8±1% papillary fractional shortening in vehicle-treated mice vs. 11.9±0.4% papillary fractional shortening in IL-2/ IL-2 mAB-treated mice; P<0.05). Survival was not different between groups. IL-2/ IL-2 mAB complex-treated animals showed an expansion of Treg cells in heart-draining lymph nodes and elevated frequencies of Foxp3-positive cells among infarct-infiltrating CD4+ T lymphocytes (41.8±5.9% Foxp3+ cells among CD4+ T cells in the infarct scar of IL-2/ IL-2 mAB-treated mice vs. 24.9±1.5% Foxp3+ cells among CD4+ T cells in the scar of control mice 7 days post-MI; P<0.05). Therapeutic injection of IL-2/ IL-2 mAB complexes provoked the expression of pro-fibrotic, M2 macrophage-inducing IL-13 in the healing myocardium evaluated 5 days after MI. Consistently, mRNA synthesis of M2-like macrophage-associated arginase 1 and CD206 as well as scar-constructing pro-collagen alpha 1 (III) were significantly upregulated in the healing infarct 5 days post-MI as compared to control mice.
Conclusion: Therapeutic Treg cell activation by IL-2/ IL-2 mAB complexes enhances postinfarction outcome and holds clinical potential for the treatment of patients with MI.
Author Disclosures: J. Weirather: None. U. Hofmann: None. N. Beyersdorf: None. T. Kerkau: None. S. Frantz: None.
- © 2014 by American Heart Association, Inc.