The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have generated floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. By using this model, we studied the effect of cell death on activation of innate immunity and liver regeneration. Cre-inducible human CD59 mediates rapid cell ablation after intermedilysin administration. Cell ablation is a powerful tool for studying cell lineage and/or function; however, current cell-ablation models have limitations. Intermedilysin (ILY), a cytolytic pore-forming toxin that is secreted by Streptococcus intermedius, lyses human cells exclusively by binding to the human complement regulator CD59 (hCD59), but does not react with CD59 from nonprimates. Here, we took advantage of this feature of ILY and developed a model of conditional and targeted cell ablation by generating floxed STOP-CD59 knockin mice (ihCD59), in which expression of human CD59 only occurs after Cre-mediated recombination. The administration of ILY to ihCD59+ mice crossed with various Cre-driver lines resulted in the rapid and specific ablation of immune, epithelial, or neural cells without off-target effects. ILY had a large pharmacological window, which allowed us to perform dose-dependent studies. Finally, the ILY/ihCD59-mediated cell-ablation method was tested in several disease models to study immune cell functionalities, hepatocyte and/or biliary epithelial damage and regeneration, and neural cell damage. Together, the results of this study demonstrate the utility of the ihCD59 mouse model for studying the effects of cell ablation in specific organ systems in a variety of developmental and disease states.
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