Abstract
Background: Mesenchymal stem cells (MSCs) become an attractive tool to suppress immune response. We have previously reported that MSC-based therapy in combination with rapamycin induced cardiac allograft tolerance in a mouse model. The present study investigated the role of MSC-expressing B7-H1 in MSC-mediated cardiac allograft protection. Methods & Results:MSCs (1×106, i.v.) from C57BL/6 donor mice were injected into BALB/c recipients 24 hours after receiving a heterotopic C57BL/6 heart graft. Grafts in untreated recipients were rapidly rejected in 7.5±0.7 days. Either MSCs or rapamycin monotherapy doubled allograft survival time to 15.8±1.5 days and 16.3±1.1 days, respectively. MSCs in combination with rapamycin induced heart allograft tolerance with normal graft histology and achieved graft mean survival time (MST) for more than 100 days. In contrast, treatment with B7-H1-blocking MSCs was not able to prolong allograft survival (MST: 8.7±1.1 days), and in combination with rapamycin prevented tolerance induction. Graft MST in the recipients treated with B7-H1-blocking MSC-based combination therapy was significantly reduced to 18.5±0.8 days. In addition, Flow cytomytry analysis showed that B7-H1 is required for MSC-mediated downregulation of antibody production and enhancement of the frequency of tolerogeneic dendritic cells (Tol-DCs) and CD4+CD25+Foxp3+ cells in tolerant recipients. In vivo treatment with MSCs expressing B7-H1 is also involved in the modulation of CD83 and cytokine (IL-4 and IL-10) expression of B cells. Furthermore, MSC-mediated suppression of B cells measured by MLR, ELISA and transwell assays requires B7-H1 and contact between CD19+ B cells and MSCs. Conclusion:This study supports a critical role of B7-H1 in MSC-mediated immunosuppression and tolerance induction in transplantation, and would clearly emphasize the significant clinical potential of MSCs.
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