Objectives:The inherent immunosuppressive properties and low immunogenicity of mesenchymal stems cells (MSCs) suggested their therapeutic potential in transplantation. In this study we investigated if systematic administration of MSCs could protect lung allograft from immune rejection and the possible mechanism.

Methods and Results:Mice orthotopic left lung transplant model was established by using C57BL/6 as donor and Balb/c as recipient. MSCs expanded from GFP+C57BL/6 mice were injected intravenously into allograft recipients at 2 hours after surgery and followed by four additional doses each day consecutively post-transplantation. Control group were injected with only PBS at the same intervals. The cyclosporine treatment group received cyclosporine 20mg/kg/d intraperitoneal injection until the experiment end time point. MSCs were trapped in the lung earlier time after being injected into the mice and a few could be detected in the graft lung till day 21 after transplant. GFP-MSCs were also detected in the spleen and lymph nodes. The grade of acute rejection was histopathologically evaluated. There was no significant difference of rejection grade between MSCs group and cyclosporine group which were significantly better than PBS group at day 7 and 14. At day 21 after surgery, the rejection grade of MSCs group increased compared to cyclosporine group but was still better than PBS group. The lung grafts were removed and graft infiltration lymphocytes were isolated. The percentages of CD4+CD25+FOXP3+Treg and CD8+IFN-γ+Tc were assessed by flow cytometry assay. The percentage of Treg in MSCs group is much higher than in PBS group. The percentage of Tc in MSCs group is lower than in PBS group. The splenocytes were obtained for enzyme-linked immunosorbent spot (ELISPOT) assay to test recipient immune response type. ELISPOT results showed that IFN-γ spots were decreased in MSC group, IL-4 spots were increased in MSCs group.

Conclusion: The experiment have shown that MSCs could migrate into graft lung. Multiple dose administration of MSCs can protect the lung allograft from acute rejection. The mechanism is related to T regulatory cells induction, reduction of cytotoxic T lymphocyte and Th1 to Th2 immune response deviation.

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