IL-18BP Improves Early Graft Function and Survival in Lewis-Brown Norway Rat Orthotopic Liver Transplantation Model

Interleukin-18 (IL-18) can effectively activate natural killer (NK) cells and induce large concentrations of interferon-gamma (IFN-gamma). In healthy humans, IL-18 binding protein (IL-18BP) can inhibit the binding of IL-18 to IL-18R and counteract the biological action of IL-18 due to its high concentration and high affinity, thus preventing the production of IFN-gamma and inhibiting NK-cell activation. Through previous studies and the phenomena observed by our group in pig-non-human primates (NHPs) liver transplantation experiments, we proposed that the imbalance in IL-18/IL-18BP expression upon transplantation encourages the activation, proliferation, and cytotoxic effects of NK cells, ultimately causing acute vascular rejection of the graft. In this research, we used Lewis-Brown Norway rat orthotopic liver transplantation (OLTx) as a model of acute vascular rejection. AAV8-Il18bp viral vectors as gene delivery vehicles were constructed for gene therapy to overexpress IL-18BP and alleviate NK-cell rejection of the graft after transplantation. The results showed that livers overexpressing IL-18BP had reduced damage and could function longer after transplantation, effectively improving the survival time of the recipients.

Automated summary

Interleukin-18 (IL-18) can activate NK cells and induce IFN-gamma production. IL-18BP can inhibit IL-18 binding and counteract its biological action. Imbalance in IL-18/IL-18BP expression during transplantation promotes NK cell activation and rejection. Gene therapy with IL-18BP overexpression can alleviate rejection and improve graft survival.