Mesenchymal Stem Cells Combined With Low-dose Rapamycin Prolong Islet Grafts Survival In Mice Through Differential Mediate Regulatory T Cells And Effector T Cells

Aims/hypothesis:The aim of this study was to determine whether therapy of MSCs,either alone,or combined with Rapamycin could used to prolong the survival of fully MHC-mismatched mice islet allografts.Methods:STZ-induced diabetic C57BL/6 mice(H2~b)were transplanted with pancreatic islets from BALB/c mice(H2~d).Recipients were treated with intra-peritoneal administration of C57BL/6 MSCs,in the presence or absence of Rapamycin.Blood glucose levels was monitored until rejection occurred,as defined by blood glucose levels>14.5mmol/l for at least 2 consecutive days.At 9 days post-transplant,intra peritoneal glucose tolerance tests were carried out to assess the function of islet grafts.Graft inflammatory infiltrate were evaluated by immunohistochemistry and intergraft regulatory T cells by immunofluorescent staining.Results:Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts,whereas treatment of MSCs,or Rapamycin alone,had no impact.The protective effect of the MSCs and Rpamycin combined therapy was correlated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes,a skewed T-cell differentiation toward immunotolerance,and a profound suppression of alloreactivity against donor antigen.Conclusions/interpretation:Our study suggested that a combination therapy of MSCs and Rapamycin prolonged the survival and enhances the function of islet allograft in the fully MHC-mismatched mice model of islet transplantation.