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Control of hepatic T cell responses in biliary atresia

胆道闭锁中肝 T 细胞反应的控制

基本信息

批准号：
10133058
负责人：
Alexander Miethke
金额：
$ 41.29万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133058
关键词：
ABCB1 gene Acute Adjuvant Therapy Agonist Anti-Inflammatory Agents Archives Attenuated Bile Acids Bile Duct Epithelium Bile fluid Biliary Biliary Atresia Bilirubin Biological Markers Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Candidate Disease Gene Cells Childhood Cholestasis Chronic Clinical Clinical Data Cluster Analysis DNA Methylation Data Dendritic Cells Diagnosis Drainage procedure Duct (organ) structure Epigenetic Process Epithelial Etiology FOXP3 gene Fibrosis Funding Future GPBAR1 gene Gene Expression Gene Expression Profile Genes Grant Hepatic Hepatobiliary Hepatology Homeostasis Icterus Image Analysis Immune Immune response Immunofluorescence Immunologic In Vitro Infant Inflammatory Injury Intestines Intrahepatic bile duct Knockout Mice Kupffer Cells Leukocytes Lipids Liver Liver Fibrosis Liver diseases Lymphocyte Lymphocyte Activation Mediating Molecular Molecular Target Mononuclear Mus National Institute of Diabetes and Digestive and Kidney Diseases Natural Killer Cells Neonatal Obstruction Operative Surgical Procedures Outcome Parents Pathway interactions Patients Pharmacology Phenotype Population Pre-Clinical Model Process Production Publishing Regulation Regulatory T-Lymphocyte Reporting Research Rotavirus STAT3 gene Sclerosing Cholangitis Serum Shapes Surveys T cell response T-Lymphocyte Testing Time Tissues Validation Work base bile duct biliary tract clinical phenotype cohort cytokine efflux pump epigenetic silencing epithelial injury experimental analysis experimental study human disease improved individualized medicine intrahepatic liver biopsy liver injury mRNA Expression macrophage mouse model neonate new therapeutic target novel osteopontin patient subsets polarized cell prospective receptor recruit response restoration reuptake segregation surgery outcome targeted treatment therapeutic target transcription factor transcriptome transcriptome sequencing uptake

项目摘要

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 will interrogate segregation of clusters defined by integrated RNAseq- and immunofluorescence - based enumeration of liver infiltrating T cells with BA phenotype and HPE outcome.

项目摘要/摘要