Induction of long-term liver allograft survival by delayed immunosuppression is dependent on interleukin-10.
This study aims to investigate the potential role of endogenous interleukin (IL)-10 in long-term liver allograft survival induced by delayed immunosuppression (FK506 days 2-7). Liver transplantation was performed by using Dark Agouti and Lewis rats as donors and recipients, respectively. The delayed immunosuppression protocol induced indefinite allograft survival. A transient upregulation of plasma IL-10 levels was detected in the nontreatment and FK506 treatment groups. Macrophages were found to be one of the major sources of IL-10 produced from the liver allografts. Administration of IL-10-neutralizing antibody shortened the long-term isograft survival and FK506-induced indefinite allograft survival, particularly in the FK506 group. Damaged liver graft histology and increase of plasma alanine aminotransferase levels were detected in the groups with IL-10 antibody treatment. In an ex vivo setting, IL-10 recombinant protein augmented the expression of Foxp3, downregulated the expression of IL-2 and interferon gamma, and induced the generation of CD4(+)CD25(+)Foxp3(+) and CD8(+)CD25(+)Foxp3(+) cells, but this effect was blocked by the administration of IL-10 antibody. Finally, administration of IL-10 recombinant protein after the decline of endogenous IL-10 levels improved allograft survival, and a 100% long-term allograft survival was achieved by the combination of IL-10 with low-dose FK506. In conclusion, the delayed immunosuppression could induce long-term liver allograft survival in the presence of endogenous IL-10 produced by the tissue macrophages. Supplementary exogenous IL-10 administration combined with low-dose immunosuppressive drug may be a useful strategy to induce long-term liver allograft survival.
Yang
Zhen Fan
ZF
Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong, China. zfyang@hkucc.hku.hk
Ngai
Patricia
P
Lau
Chi Keung
CK
Ho
David W
DW
Tam
Ka Ho
KH
Lam
Chi Tat
CT
Poon
Ronnie T
RT
Fan
Sheung Tat
ST
D000818:Animals; D018929:Cell Culture Techniques; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D016753:Interleukin-10 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008111:Liver Function Tests; D016031:Liver Transplantation / Q000276:immunology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014184:Transplantation, Homologous
D016753:Interleukin-10; D012313:RNA; D016559:Tacrolimus