The Mechanism Of Murine Allograft Survival Mediated By FLT3L Combination With Low-dose Rapamycin

Background:The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. In this study, we investigate the role and mechanisms of the combination therapy of Flt3L and low-dose rapamycin (Rapa) in promoting the cardiac allograft tolerance.Methods:The C57BL/6recipient mice were pretreated with Flt3L (10μg/day, i.v) for10consecutive days before MHC-mismatched cardiac transplant using hearts from BALB/c donor mice, and then the recipients were treated with Rapa (2mg/kg/day; p.o, POD0-15) after transplantation. The graft survivals were monitored, and the T cells, DC phenotypes were measured by flow cytometric analysis. The function of T cells of recipient animals was examined by mixed lymphocytes reaction (MLR). The expression of autophagy related protein (beclin-1, LC3) was evaluated by Western blot analysis and immunohistochemistry.Results:Treatment of the recipients with Flt3L in combination with Rapa significantly abated rejection and prolonged the graft survival time as compared to those of untreated, Rapa alone or Flt3L alone treated recipients. The prolonged graft survival is associated with augmentation of the generation of regulatory DC subsets, CD25+Foxp3+regulatory T cells (Tregs) and increased the production of suppressive cytokines IL-10. Moreover, we found that enhanced autophagy of cardie allograft contribute to allograft protection by administration of Flt3L combined with Rapa.Conclusion:Flt3L in combination with Rapa could be used as a therapeutic approach to promote transplantation tolerance.