# Control of hepatic T cell responses in biliary atresia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $412,863

## Abstract

Project Summary/ Abstract
Biliary atresia (BA) refers to idiopathic obliteration of the biliary tree in neonates. Unfortunately, up to 50% of
infants who undergo attempts at surgical restoration of bile flow by hepatoportoenterostomy (HPE) remain
cholestatic and rapidly progress to end-stage liver disease. Potential therapeutic targets include hepatic NK,
CD8 and Th17-lymphocytes which have been identified as drivers of inflammatory ductal obstruction and
progressive injury of the intrahepatic biliary epithelium. Our group has reported that regulatory T cells (Tregs)
are able to restrain hepatic lymphocyte responses protecting from bile duct injury and initiation of liver fibrosis.
Therefore, we explored the mechanisms controlling Treg/Th17 homeostasis under cholestatic conditions
recapitulating progressive BA. Our preliminary findings demonstrate that conjugated bile acids (CBA) repress
expression of the Treg- transcription factor Foxp3 and inhibit Treg-function in vitro. In the Mdr2-/- mouse model
of “toxic bile” induced progressive cholestasis, inhibition of intestinal bile acid reuptake resulted in dramatic
reduction in serum bile acid concentration which shifted cytokine production by Kupffer cells accompanied by
rapid hepatic expansion of Tregs. In rotavirus induced murine BA, treatment with Fxr agonists induced
expression of Il-10 in hepatic mononuclear cells, expanded Tregs, and attenuated the BA phenotype. We
hypothesize that bile acids are epigenetic modifiers that control Treg homeostasis and determine the
inflammatory microenvironment in the liver through activation of the bile acid receptors Tgr5 and Fxr. We will test
this hypothesis by investigating the molecular mechanisms mediating bile acid induced silencing of Foxp3 in
vitro and by deleting candidate molecular targets for CBA in CD4 lymphocytes in mice with acute or chronic
cholestasis (Aim 1). In Aim 2, the effects of activation of Tgr5 and Fxr on regulation of macrophage derived
cytokine production and Treg homeostasis, and on the fibrosing cholangiopathy phenotype will be studied in
bone marrow transplant experiments and in conditional bile acid receptor knockout mice. For validation in human
disease, we will investigate whether hepatic T lymphocyte responses are associated with distinct clinical
phenotypes by analyzing liver RNAseq and clinical data and performing immunofluorescence and image analysis
on archived liver biopsies from an inception cohort of 203 patients with BA followed by the multicenter Childhood
Liver Disease Research Network (Aim 3). In preliminary studies we generated a gene list of Th17 associated
genes from in vitro polarized neonatal Th17 lymphocytes. Hierarchical cluster analysis of these experimentally
derived Th17 candidate genes in liver RNAseq data from 137 patients with BA revealed clusters of patients with
similar gene expression profile. Serum conjugated bilirubin levels differed between these clusters, supporting
our hypothesis. Future studies...

## Key facts

- **NIH application ID:** 9962379
- **Project number:** 5R01DK095001-07
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Alexander Miethke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,863
- **Award type:** 5
- **Project period:** 2012-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962379

## Citation

> US National Institutes of Health, RePORTER application 9962379, Control of hepatic T cell responses in biliary atresia (5R01DK095001-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962379. Licensed CC0.

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