Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow- derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10+ and IFN-γ+ cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL-10+IFN-γ+CD4 + regulatory T type 1 (TR1)-like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10+IFN- γ+CD4+ cells, which confer resistance to allogeneic proliferation in an IL-10-dependent manner, resemble TR1-like cells. Both cyclooxygenase-derived PGE2 and IDO help to induce T R1-like cells by MSCs. MSCs constitutively secrete PGE2, which is augmented in allogeneic reactions. However, TR1-like cells were deficient in PGE2 and 4-fold less potent than were MSCs in suppressing MLR. PGE2 mimetic supplements can enhance the immunosuppressive potency of TR1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced TR1-like cells combined with PGE2, but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: TR1-like cells + PGE2: 11 6 10%; PGE2 alone: 93 6 8.7%; T R1-like cells alone: 88 6 2.4% versus untreated 94 6 0.9%, p <0.001). These findings indicate that PGE2 helps MSC-induced IL-10+IFN-γ+CD4+ TR1-like cells inhibit TA. PGE2 combined with MSC-induced TR1-like cells represents a new approach for achieving immune tolerance.
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