How can you predict immune-mediated liver injury following drug dosing?
Immune-mediated liver injury is caused by activation of inflammatory pathways, making the liver more sensitive to insults. In particular, new modality drugs, such as monoclonal antibodies, can activate the peripheral immune system to initiate a cascade of liver damage.
Immune-mediated liver injury is currently challenging to predict as the cause of the hepatic injury is often complex, interaction-based, and situation-specific. Therapeutics that act via the immune system, such as monoclonal antibodies for cancer, can under- or over-activate the immune system, causing increased autoimmunity or reactivation of liver viruses such as hepatitis B.
Traditional in vitro models do not facilitate the co-culture of liver cells with circulating immune cells, provide the longevity to explore chronic inflammation effects or enable the impact of underlying disease states on immune-mediated liver injury to be evaluated. In vivo models have unique immune systems which do not naturally recapitulate humans. In addition, stress from living in the laboratory setting and research can significantly impact metabolism, inflammatory responses and disease progressions.
Our solution
By incorporating immune cells into PhysioMimix® Liver-on-a-chip models, detailed mechanistic studies of the condition in the presence of various inflammatory cues and disease can now be performed to flag the immune-mediated liver injury risk of small molecules or biologics.
The tissue-resident macrophages of the liver (Kupffer cells) are cocultured with primary human hepatocytes to determine liver-specific inflammatory response as part of our PhysioMimix Drug-induced liver injury (DILI) assay.
Additionally, by including peripheral immune cells into the circulating media of the Liver-12 plate, it is possible to determine interactions between the immune system and the liver to identify adverse effects on hepatic health, function or changes to the inflammatory profile.
Using PhysioMimix disease models, drugs can also be tested against common liver disorders such as Hepatitis B and MASLD/MASH to identify patient cohorts with increased DILI susceptibility due to underlying inflammatory disease.
These capabilities enable you to future-proof your testing workflows in response to the FDA’s plans to phase out the animal testing requirement for monoclonal antibodies and other drugs with more human-relevant models. We are currently looking for partners to further validate the assay. Please contact us if you would like to participate.
Studying immune-mediated liver injury
Limitations with current techniques
- Challenging to study immune-tissue level interaction in vitro
- Poor in vitro to in vivo data translation
- Unable to recapitulate inflammation driven by disease
- Challenging to run acute and chronic exposure assays due to short-lived cultures
Advancements with PhysioMimix OOC
- Immune cells can be incorporated into and circulate around liver microtissues
- Measurement of clinical biomarkers (e.g. ALT/AST) allows for direct comparison to in vivo data
- Inflammation can be induced through disease state, e.g. MASLD/MASH
- Long-term stable tissues enable repeat compound dosing
End point measurements
Longitudinal and endpoint measurements include (but not limited to):
Functionality biomarkers
- Cytochrome P450 enzyme activity
- Albumin production
- Urea production
- Cytokine/chemokine release
Clinical liver health biomarkers
- Lactose dehydrogenase (LDH) release
- Adenosine Triphosphate (ATP)
- Aspartate Transferase (AST)/Alanine amino transferase (ALT)
Optional profiling analysis
- Quantitative PCR
- Transcriptomics
- Flow cytometry
Discern immune-mediated liver injury
Following exposure to pro-inflammatory stimuli, liver microtissues produce a range of physiologically relevant cytokines, chemokines, and growth factors that can be altered using different stimuli or inducing disease states.
Flagging enhanced DILI risk due to inflammation
The effect of inflammation on DILI sensitivity is assessed by testing therapeutics with or without specific immunomodulators (e.g., LPS).
Detect immune-organ inflammatory events
Include peripheral immune cells and measure multiple soluble markers over time to understand interactions between multiple organs during inflammatory adverse events. Detect acute phase response proteins, like albumin and C-reactive protein (CRP), and predict cytokine storm events.
Explore our Liver-on-a-chip models
Recreate the 3D multi-cellular architecture of the liver using perfused scaffolds. Achieve longer-term viability, enhanced functionality & high metabolic activity.
Access our DILI Service
Get instant access to the immune-mediated DILI Assay via our CRO Service. Through a collaborative approach, our experts work with you to plan and execute your study.
Bespoke projects are carried out by our dedicated team of scientists in our CRO facility providing you with actionable data within weeks.
Add PhysioMimix OOC to your lab
Harness the power of PhysioMimix OOC in your own lab with the purchase of a single- or multi-organ microphysiological system.
With a growing community of users and support from our experts, there has never been a better time to transition into 3D cell culture.
