Flt3L combined with rapamycin promotes cardiac allograft tolerance by inducing regulatory dendritic cells and allograft autophagy in mice.
The induction of immune tolerance is still a formidable challenge in organ transplantation. Dendritic cells (DCs) play an important role in orchestrating immune responses by either mediating protective immune responses or inducing antigen specific tolerance. Previous studies demonstrated that the fms-like tyrosine kinase 3 receptor (Flt3) and its ligand (Flt3L) play an essential role in the regulation of DC commitment and development. Here, we report a synergic effect between Flt3L and low-dose rapamycin (Rapa) in the protection of allograft rejction. It was found that Flt3L combined with Rapa significantly prolonged murine cardiac allograft survival time as compared with that of untreated recipients or recipients treated with Rapa or Flt3L alone. Mechanistic studies revealed that Flt3L combined with low-dose of Rapa induced the generation of tolerogenic DCs along with the production of CD25(+) Foxp3(+) regulatory T cells and IL-10 secretion. We also observed enhanced autophagy in the cardiac allograft, which could be another asset contributing to the enhanced allograft survival. All together, these data suggest that Flt3L combined with low-dose of Rapa could be an effective therapeutic approach to induce tolerance in clinical setting of transplantation.
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Ali
A
Xiong
Lihua
L
Duan
Jie
J
Chen
Zhigang
Z
Fan
Fang
F
Zheng
Zheng
Z
Tan
Feili
F
Gong
Min
M
Fang
D000818:Animals; D001343:Autophagy; D003713:Dendritic Cells / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020123:Sirolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
D008565:Membrane Proteins; C084881:flt3 ligand protein; D020123:Sirolimus