Abstract 18331: Systemic Administration of Allogenic Fetal Membrane-derived MSC Ameliorates Experimental Autoimmune Myocarditis via Suppression of Th1/Th17 Immunity
Background: We have reported that systemic administration of autologous bone marrow or allogenic fetal membrane (FM)-derived mesenchymal stem cells (MSCs) similarly attenuated experimental autoimmune myocarditis (EAM) (JMCC 42:88-97 2007, 49:753-61 2010). Since rat EAM is a T-helper (Th) cell-mediated autoimmune disease, and recent evidence has indicated that MSCs exert an immunosuppressive effect on Th cell activity, we focused on Th cell differentiation in allogenic FM-MSC administered EAM rats.
Methods and Results: EAM was induced in Lewis rats by injecting porcine cardiac myosin (day 0). Allogenic FM-MSCs, obtained from major histocompatibility complex mismatched ACI rats, were intravenously injected (5×10[[Unable to Display Character: ⁵]] cells/rat) on day 7, 10, or 14 (MSCd7, MSCd10, or MSCd14 groups, respectively). At day 21, echocardiography confirmed that reduced ejection fraction in the untreated EAM group (63±2%) was significantly improved in the MSCd10 and MSCd14 groups (74±1 and 75±2%, respectively, P<0.01). CD68 immunostaining revealed that prominent macrophage infiltration in the myocardium of the EAM group (1466±93 cells/mm²) was significantly decreased in the MSCd10 group (958±139 cells/mm², P<0.05). To evaluate Th cell differentiation, flow cytometry was performed to determine the percentage of interferon (IFN)-γ positive Th1 and interleukin (IL)-17 positive Th17 cells in peripheral CD4-positive Th cells. The percentage of Th1 cells at day 16 was significantly lower in the MSCd10 (1.3±0.2%) and MSCd14 (1.6±0.3%) groups compared to the EAM group (2.4±0.3%, P<0.05), as was the percentage of Th17 cells in the MSCd10 group (1.9±0.5%) compared to the EAM group (2.2±0.9%, P<0.05). In addition, human CD4+ Th cells co-cultured with human FM-MSCs exhibited reduced Th1 and Th17 cell differentiation and proliferation, with increased expression of immunosuppressive molecules including indoleamine 2,3-dioxygenase 2 and IL-6 in co-cultured FM-MSCs.
Conclusion: Our findings demonstrate the protective effects of intravenously administered FM-MSCs in EAM due to profound suppression of Th1/Th17 cells and provide a new perspective for the treatment of acute myocarditis.
- © 2012 by American Heart Association, Inc.