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Anti-CD8a, anti-IL-17A antibodies improved immune disruption in mice with history of NASH

Key clinical point: Anti-CD8a and anti–interleukin-17A antibodies helped attenuate diet-refractory inflammatory changes in mice with a history of nonalcoholic steatohepatitis.

Major finding: Diet reversal normalized body weight and various clinical parameters in mice with NASH, but immune disruptions in T cells persisted. Treatment with anti-CD8a antibodies decreased cytotoxic T cells in all tissues tested, while antibodies targeting IL-17A reduced hepatic inflammation.

Study details: High-fat, high-fructose diet feeding followed by diet reversal to standard mouse chow and administration of anti-CD8a and anti-IL-17A antibodies. Assessments of plasma ALT, glucose, and lipid levels. Tissue histology and flow cytometry and RNA analyses of T cells in liver and visceral adipose tissue.

Disclosures: Funders included the University Research Fund, University of Antwerp, and Research Foundation Flanders. The researchers reported having no conflicts of interest except that one coinvestigator is the chief science officer at Biocellvia, which performed some histologic analyses.


Van Herck MA et al. Cell Molec Gastroenterol Hepatol. 2020 Apr 20. doi: 10.1016/j.jcmgh.2020.04.010.


The trajectory of nonalcoholic steatohepatitis (NASH) is a public health watershed moment in gastroenterology and hepatology causing unparalleled morbidity, mortality, and societal costs. This study by Van Herck et al. advances our understanding of just how important a two-pronged environmental and biologic approach is to turn the NASH tide. The authors demonstrate that both dietary environmental exposure and biologic tissue-specific T-cell responses are involved in NASH pathogenesis, and that targeting one part of the equation is insufficient to fully mitigate disease. They observed that mice with more severe diet-induced NASH had more Th17 cells in the liver and visceral adipose tissue and more cytotoxic T cells in VAT. Conversely, there were fewer VAT T-regulatory cells in mice with more liver inflammation. The major novelty of this study is that simply changing the diet to a metabolically healthier and weight-reducing diet failed to correct T-cell dysregulation. Only T cell–directed therapies improved this abnormality.

The implication of their study is that, despite weight loss and improvement in liver histology and metabolic parameters, individuals with NASH may still harbor an inflammatory milieu involved in NASH pathogenesis. Perhaps this at least partially explains why the majority of NASH patients have recurrent NASH post transplant. While questions regarding NASH resurgence continue to be investigated, these data should prompt gastroenterologists and hepatologists who care for NASH patients to establish long-term care models that are focused on both adherence to dietary recommendations and monitoring of (and ultimately treatment of) systemic inflammation.

Rotonya M. Carr, MD, is an assistant professor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia. She is a hepatologist, director of the liver metabolism and fatty liver program, and codirector of the human metabolic tissue resource. Dr. Carr receives research and salary support from Intercept Pharmaceuticals.