Abstract 9280: A Targeted Delivery of Adipocytokines into the Heart by Cell-Sheet Technique Induces Immune-Tolerance and Ameliorates Cardiac Performance in Autoimmune-Associated Fulminant Myocarditis in Rat
Background: Clinical prognosis is critically poor in fulminant myocarditis, whose initiation and progression are regulated in partby autoimmune disorders. Adiponectin (APN) and associated cytokines, which have anti-inflammatory/fibrotic effects, were shown to be immune-tolerance inducers, though effective delivery methods into target pathologies have not been established. We hypothesized cell sheet-based delivery system of adipocytokines, which we recently developed, might induce immune-tolerance and functional recovery in fulminant myocarditis.
Methods and Results: Lewis rats were immunized against myosin for 7 days to develop experimental autoimmune myocarditis (EAM), which is an established fulminant myocarditis model. Scaffold-free induced adipocyte cell-sheet (iACS) was generated by inducing differentiation of syngeneic cultured adipose tissue-derived stem cells into the adipocytes on the temperature responsive dishes. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells that were sorted from splenocytes of the EAM rats, in-vitro. EAM rats underwent iACS implantation onto the anterior surface of the heart (n=24) or sham operation (n=24). Immunohistolabelling showed that CD4-positive T cells significantly less migrated in the anterior myocardium at 21 days after the iACS implantation (73±35 /mm2) than the sham (148±38 /mm2, P=0.03). This finding was consistent with reduced expression of Tnfα and Il2, assessed by real-time PCR, and elevated level of APN (48±5 ng/ml vs.5±2 ng/ml P=0.01) and HGF (37±4ng/ml vs.8±5ng/ml P=0.01), assessed by ELISA, in the myocardium after the iACS implantation compared to the sham. Consequently, left ventricular ejection fraction was significantly greater at 42 days after the iACS implantation (52±3.8%) than the sham (43±4.7%, P=0.03) in association with less myocardial collagen accumulation.
Conclusion: This tissue-engineered iACS treatment suppressed intramyocardial T cell activity and inflammation by persistently supplying adipocytokines to the heart, consequently inducing functional recovery in the EAM rat model. The findings support possible translation of this strategy into the clinical arena.
- © 2011 by American Heart Association, Inc.