Immunomodulatory Properties of Mesenchymal Stem Cells Combined with Mycophenolate Mofetil Induce T Cell Regulation and Prolong Renal Allografts Survival in Cynomolgus Monkeys

The induction of tolerance to allografts is one of the major goals in transplantation. Mesenchymal stem cells (MSCs) have been shown to be potent immunomodulatory and immunosuppressive properties in vitro and in vivo. However, to the clinical perspective of MSC-based cell therapy, it has not been clearly defined whether immunosuppressants currently utilized in the clinic may affect immunomodulatory capacities of MSCs. The aim of this study was to investigate the effect of combination therapies of MSCs and mycophenolate mofetil (MMF) on delaying acute rejection of renal allografts in Cynomolgus monkey model. MSCs were isolated from born marrow of Cynomolgus monkey. They were expanded and characterized by morphology, phenotypes and immunosuppressive functions. They were positive for CD90, CD73, CD29, CD105, and negative for CD45, CD34 and MHC-II. Monkeys received adoptive multiple infusions of autogeneic MSCs with a short-term and low-dose of MMF achieved long-term renal graft survival (>90 days post-transplantation) with normal serum creatinine (sCr) concentration and ultrasound imaging of transplanted kidney grafts. Confocal fluorescence microscopy analyses revealed that the transplanted PKH-26 labeled MSCs were found in renal allograft, spleen and lymph nodes of the recipients after the transplantation. The monkeys received MSCs showed high frequencies of CD4+CD25+Foxp3+ regulatory T cells (Tregs). An increased population of interleukin (IL) 10-secreting type 1 T regulatory (Tr1) cells and T helper (Th) 2-dominant cytokine shift were detected in survival recipients. Immunosuppressive effect of MSCs was not only showed in CD4+ and CD8+ cells, but also in their subsets of CD4+CD28+CD95- and CD8+CD28+CD95-naïve T cells. A depression in the percentages of CD4+CD28-CD95+ and CD8+CD28-CD95+ effecter memory T cells was observed in MSC treated recipients at the early stage of the treatment. In conclusion, this study shows synergistic effects of MSCs with short-term and low-dose MMF regimen in promoting renal allograft survival in Cynomolgus monkeys, also provides information to motivate the development of MSC therapy strategies in clinical transplantation.