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Large duct injury in autoimmune liver disease may stunt T cell therapy benefit
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CHICAGO — Large duct injury in pediatric patients with primary sclerosing cholangitis and autoimmune sclerosing cholangitis correlated with a distinct pattern of hepatic gene expression, which may limit benefits from T cell-directed immunosuppressive therapy, according to a study presented at NASPGHAN 2019.
“Autoimmune liver disease is a common cause of chronic liver disease in children. Currently, the biliary injury in [autoimmune liver disease (AILD)] is not responsive to immunosuppression,” Simon Lam, MD, of Cincinnati Children’s Hospital Medical Center in Ohio, said during his presentation. “Patients with biliary injury from [autoimmune sclerosing cholangitis (ASC)] and PSC have a higher proportion of complications related to liver disease compared with [autoimmune hepatitis (AIH)] at 5 years.”
Lam and colleagues enrolled 23 patients with AILD. Mean age of patients was 16 years. The researchers performed RNA sequencing and multiparameter immunofluorescence analysis on the patient biopsy samples to determine predominant hepatic immune response associated with biliary injury in autoimmune liver disease.
After grouping by gene expression, the researchers identified two main clusters.
“When we looked at cluster characteristics, we were surprised to find that the clusters didn’t segregate based on a clinical diagnosis but rather the presence of an abnormal [magnetic resonance cholangiopancreatography (MRCP)],” Lam explained.
All patients in the first cluster had abnormal MRCPs and were more likely to have large duct injury compared with 15% in the second cluster who had abnormal MRCPs and were more likely to have small duct injury.
Upregulated genes belonged to pathways correlated with increased regulatory T cell (Treg) activation and neutrophil function. Down-regulated genes correlated with bile and fatty acid metabolism, energy depletion and oxidation reduction. Additionally, patients with abnormal MRCP had more Tregs per area of tissue compared with MRCP according to immunofluorescence assessment.
found that the levels of pathogenic Th17.1 cells, which secrete pro-inflammatory cytokines and are glucocorticoid resistance, were higher in the first cluster compared with the second cluster (73% vs. 31%; P < .001), but both clusters had similar Th17 and Th17.1 to Treg ratios.
“This suggests that the expansion of Th17 and Th17.1 are not necessarily related to an overall decrease in regulatory T cells,” Lam said.
Lam concluded that children with large duct disease have a unique gene expression profile entrenched with Th17 and Th17.1. Additionally, IL-17 pathways may represent novel therapeutic drug targets for patients with large duct disease. – by Talitha Bennett
Reference:
Lam S, et al. Abstract 215. Presented at: NASPGHAN; October 17-19, 2019; Chicago.
Disclosures: Lam reports no relevant financial disclosures.