Human liver immunology: from in vitro models to new insights

The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.