Abstract 14885: Blocking VCAM-1/VLA-4 Axis Ameliorates Inflammation and Fibrosis in Experimental Autoimmune Myocarditis
Introduction: During inflammation, Vascular Cell Adhesion Molecule-1 (VCAM-1) is strongly upregulatedin the inflamed tissue. VLA-4, an integrin which binds to VCAM-1, is expressed on all subpopulations of leukocytes and VCAM-1/VLA-4 interaction is predominantly involved in leukocyte trafficking and extravasation. Aim: We assessed the hypothesis that blocking VCAM-1/VLA-4 axis in a murine model of experimental autoimmune myocarditis (EAM) with a VLA-4 antibody can limit migration of inflammatory cells to the heart and therefore ameliorate myocarditis in a model of experimental autoimmune myocarditis.
Methods: We therefore immunized 6-8 week old Balb/c-mice with cardiac myosin and CFA. After 21 days, mice developed an inflammation of the myocardium. VCAM-1 expression in the inflamed heart was verified by ELISA. The animals where then treated with a VLA-4 antibody or with saline. We determined the grade of leukocyte infiltration and fibrosis after 4 weeks of treatment by histological analysis. The migrated CD45+ cells in the heart where further analysed by FACS.
Results: VCAM-1 is strongly upregulated during the progress of EAM. Treatment with a VLA-4 antibody for 4 weeks is sufficient to ameliorate the grade of EAM. It significantly decreases T-cell relapse for more than one degree (EAM-score 1.8 (+/- 0.3) in saline vs. 0.7 (+/-0.4) in VLA-4 antibody treated group) at day 49. Further, fibrosis of the myocardium is significantly reduced by 64.7% (1.7% (+/-0.95%) in saline vs. 0.6% (+/-0.5) in VLA-4 antibody treated group).
Conclusion: This is the first study to show that blocking of the VCAM-1/VLA-4 axis can improve T-cell relapse and fibrosis in the chronic state of EAM when treatment is started at the peak of inflammation (day 21). Since VLA-4 antibodies are clinically applicable drugs, our results have direct impact on the transfer of our therapeutic approach from bench to bedside.
- © 2012 by American Heart Association, Inc.