Drug discovery requires in vitro models to study disease progression and screen new drug candidates. But it can be particularly challenging to develop predictive models for diseases with complex etiologies and multiple disease states. Conventionally, liver models have been relatively short-term monocultures of hepatocytes. While these models continue to have wide application for many types of studies, more complex models — that integrate numerous cell types — give researchers new tools to understand the mechanisms of disease, evaluate potential medicines and predict in vivo toxicity and drug-drug interactions (DDIs).
BioIVT recently added high-purity Kupffer cells to its portfolio of hepatocytes and other human hepatic products. High-purity Kupffer cells, in addition to BioIVT’s other non-parenchymal cell (NPC) products, are used in monocultures, co-cultures and microtissue configurations. For example, BioIVT’s HEPATOMUNE® product, a 3-way culture of micropatterned hepatocytes, stomal cells and Kupffer cells, provides a unique, long-term model to study hepatic inflammation. Additionally, BioIVT’s Kupffer cells are used in spheroid cultures that are commercially available or developed by clients in their own labs. These systems, along with disease models, can provide deeper insights into hepatotoxicity, metabolism and drug-induced liver injury (DILI).
High-Purity Kupffer Cells: A Novel Tool To Enhance In Vitro Models
Kupffer Cells in Hepatic In Vitro Disease and Tox Models to Predict Inflammatory Response
There is a growing investment in developing therapies for hepatic diseases, such as NAFLD and NASH. That has driven interest in developing in vitro models that incorporate Kupffer cells.
Immune activation, and the resulting inflammation, is an important component of liver health. Immune activation as a result of infection or other liver injury allows the liver to clear any pathogens and resolve damage through regeneration. However, dysregulation of the inflammation response is a driving component of numerous liver diseases. Liver NPCs, including Kupffer cells, orchestrate these immune responses. Kupffer cells, the resident macrophages of the liver, are localized to the hepatic sinusoid, allowing them to perform a surveillance role by enabling the liver to respond to pathogens and damage. The plasticity of the Kupffer cells’ response allows them to precisely regulate inflammation through phenotypic changes, resulting in differential expression of pro- or anti- inflammatory mediators. This critical regulation of inflammatory response by Kupffer cells makes them an important component of in vitro models of liver disease, as well as in vitro screening models for drug toxicity arising from inflammation-induced down-regulation of drug metabolizing enzymes (DME) and/or drug transporters.
Kupffer Cells to Predict Drug-Induced Liver Injury
Kupffer cells are an important element in cases of drug-induced liver injury (DILI), but due to their heterogeneity, their role in DILI is complex, and they can both protect against DILI as well as cause it. Evidence suggests that for some drugs, Kupffer cells protect the liver from DILI by releasing hepatoprotective cytokines, including IL-10 and IL-6.1 For other drugs, Kupffer cells have been shown to significantly contribute to DILI through the release of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, which can be either protective or damaging depending on the context.1,2 In some cases, the propensity of a drug to induce DILI may only be unveiled in vitro when Kupffer cells are present and directed toward a pro-inflammatory response. For example, studies performed at BioIVT demonstrated a significant increase in toxic response to hepatotoxic drugs such as trovafloxacin and clozapine when Kupffer cells were present in in vitro models with hepatocytes and induced to a pro-inflammatory state using lipopolysaccharide (LPS). In a study examining trovafloxacin, this effect was mediated by TNF-α, which corresponds with in vivo findings.3 These studies highlight the ability of in vitro models containing Kupffer cells to improve the replication and prediction of in vivo findings.
REFERENCES
- M. Barnes, L. J. Dixon, Z. X. Liu, H. Tang, L. N.-D.-I. L. Disease, and 2013, “Macrophages and Kupffer Cells in Drug-Induced Liver Injury,” 2013.
- S. Li, M. Hong, H. Y. Tan, N. Wang, Y. F.-O. medicine and …, and 2016, “Insights into the role and interdependence of oxidative stress and inflammation in liver diseases,” 2016.
- P. J. Shaw, K. M. Beggs, E. S.- Toxicological …, and 2009, “Trovafloxacin enhances TNF-induced inflammatory stress and cell death signaling and reduces TNF clearance in a murine model of idiosyncratic hepatotoxicity,” 2009.