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Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
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CD40 agonist-induced IL-12p40 potentiates hepatotoxicity
Caroline Bonnans1, Graham Thomas1, Wenqian He1
1Cancer Immunology Discovery, Pfizer Inc, San Diego, California, USA.
Journal for Immunotherapy of Cancer
|June 1, 2020
Summary
CD40 agonists show promise for cancer immunotherapy but cause toxicity. This study reveals that hepatotoxicity and cytokine release syndrome (CRS) are independent, driven by distinct inflammatory networks, not IL-6.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- CD40 agonists are promising cancer immunotherapy targets.
- Clinical application is limited by dose-limiting toxicities like hepatotoxicity and cytokine release syndrome (CRS).
Purpose of the Study:
- Investigate the mechanisms of CD40 agonist-induced hepatotoxicity and CRS.
- Identify key molecular players in CD40-mediated toxicities.
Main Methods:
- Utilized cytokine and cytokine receptor depletion strategies.
- Administered a potent CD40 agonist in preclinical models.
- Assessed liver enzymes, myeloid cell activation, and cytokine profiles.
Main Results:
- CD40 agonist-induced hepatotoxicity and CRS are mechanistically distinct.
- CRS is mediated by an inflammatory network including TNF, IL-12p40, and IFNγ, not IL-6.
- IL-12p40 deficiency reduced liver enzyme levels and myeloid cell activation in the liver.
Conclusions:
- Understanding the distinct mechanisms of CD40 agonist toxicity is crucial.
- Targeting specific inflammatory pathways may mitigate toxicity.
- Developing safer CD40 agonists requires knowledge of their antitumor functions and toxicity mediators.
