Adoptive transfer of FTY720-treated immature BMDCs significantly prolonged cardiac allograft survival.
A sphingosine 1 phosphate receptor modulator, FTY720, has been used to alleviate symptoms in allotransplantation and autoimmune disease models with impressive efficacy, while it only achieved moderate success in clinical trials. Infusion of immature bone marrow-derived dendritic cell (BMDC) progenitors before transplantation could induce donor specific tolerance. In this study, we investigated the possibility of using FTY720-DCs (FTY720-treated immature BMDCs) to prevent severe alloimmune response. Our results indicate that FTY720-DCs could markedly prolong graft survival compared with Ctrl-DCs (nonconditioned immature BMDCs) as manifested by reduced inflammatory infiltration into the graft. IFN-γ production by CD4(+) and CD8(+) T cells were significantly reduced, while FoxP3(+) regulatory T cells among CD4(+) T cells were upregulated. Although FTY720 seldom altered the phenotype or the phagocytosis of BMDCs in vitro, it severely hampered their capability to trigger antigen-specific and allogeneic T-cell response. When splenic T cells were co-cultured with FTY720-DCs, the proportion of regulatory T cells increased, accompanied by elevated IL-10 production. Consistently, infusion of FTY720-DCs could preferentially promote Treg proliferation and upregulate PD-1 expression on conventional T cells in allogeneic mature BMDC priming experiment. These results suggest that infusion of FTY720-DCs before cardiac transplantation could significantly prolong functional graft survival by acting as a balancer of alloimmune response.
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yang
Y
Heng
Yuting
Y
Ma
Hui
H
Yin
Lihua
L
Duan
Ping
P
Xiong
Yong
Y
Xu
Wei
W
Feng
Min
M
Fang
Zheng
Z
Tan
Yifa
Y
Chen
Fang
F
Zheng
Feili
F
Gong
D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000637:transplantation; D005260:Female; D000068876:Fingolimod Hydrochloride; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011409:Propylene Glycols; D007371:Interferon-gamma; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine