A liver-immune coculture array for predicting systemic drug-induced skin sensitization.

Area of Science:

• Toxicology
• Immunology
• Drug Development

Background:

• Drug-induced skin sensitization is a significant global health concern, potentially leading to severe conditions like Stevens Johnson Syndrome.
• Current in vitro models struggle to predict systemic drug sensitization due to the complex interplay of liver metabolism and immune activation preceding skin reactions.

Purpose of the Study:

• To develop and validate a novel compartmentalized liver-immune coculture array capable of predicting skin sensitization potential of systemically administered drugs.
• To recapitulate the early tandem cellular processes involving drug metabolism in the liver and subsequent immune system activation.

Main Methods:

• A microfluidic coculture system was designed with human hepatocyte spheroids (HepaRG) and U937 myeloid cells (antigen-presenting cells) in concentric micro-chambers connected by diffusion channels.
• Paradigm sensitizing drugs (carbamazepine, phenytoin, allopurinol) and a non-sensitizer were administered to assess metabolite diffusion and U937 cell activation over 48 hours.
• U937 activation was quantified by measuring upregulation of IL8, IL1β, and CD86.

Main Results:

• The liver-immune coculture array successfully metabolized paradigm sensitizing drugs into reactive metabolites that diffused into the immune compartment.
• The system demonstrated higher consistency and reliability in distinguishing sensitizing drugs from non-sensitizers compared to conventional Transwell cocultures.
• U937 activation markers (IL8, IL1β, CD86) effectively indicated the sensitizing potential of the tested drugs.

Conclusions:

• The compartmentalized liver-immune coculture array accurately predicts skin sensitization potential by simulating early systemic drug reaction mechanisms.
• This miniaturized, simple, and predictive in vitro system is suitable for scaling into a high-throughput platform for identifying systemic drug sensitizers.