Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation.
Current immunosuppressive strategies for transplantation have failed to achieve long-term graft survival. In this study, we investigate the effects of combined treatment with triptolide (TPT) and rapamycin (Rapa) on graft survival as well as changes in pathology and immunological responses. Heterotopic heart transplantation was performed. TPT and Rapa were administered either alone or in combination. The mean survival time (MST) for the cardiac allografts in animals receiving the combination of TPT and Rapa was 93.5 +/- 6.7 days compared to treatment with TPT (MST: 23.5 +/- 5.3 days), Rapa (22 +/- 1.3 days) alone or no treatment (7.66 +/- 0.8 days). Histopathological evaluation showed that inflammatory cell infiltration was markedly reduced in grafts with combined treatment groups. Down-regulation of CCL19, CCR5, CCR7, interferon gamma and interleukin (IL)-12 in the combination treatment was accompanied by increased expression of IL-4, IL-10 and CD4(+)CD25(+)Foxp3(+) regulatory T (Tr) cells in spleen. Finally, dendritic cell (DC) maturation was impaired by treatment with TPT/Rapa. Our results demonstrate that combination therapy with TPT and Rapa markedly prolongs cardiac allograft survival. This effect is accompanied by inhibition of DCs maturation, conditioning DCs to adopt tolerogenic phenotype, and the expansion of Tr cells. These results add weight to the application of combination therapy in transplantation.
Liu
Yan
Y
Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China.
Chen
Yan
Y
Liu
Fing Qin
FQ
Lamb
Jonathan R
JR
Tam
Paul K H
PK
D000818:Animals; D054415:Chemokine CCL19 / Q000032:analysis; D054421:Chemokine CCL21 / Q000032:analysis; D003713:Dendritic Cells / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010616:Phenanthrenes / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014184:Transplantation, Homologous
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D004224:Diterpenes; D004852:Epoxy Compounds; D007166:Immunosuppressive Agents; D010616:Phenanthrenes; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; C001899:triptolide; D015847:Interleukin-4; D020123:Sirolimus