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854
TENOFOVIR ALAFENAMIDE DECREASES ALT IN CHRONIC
HEPATITIS B PATIENTS PRIOR TO A REDUCTION IN
INTRAHEPATIC IMMUNE ACTIVATION ASSESSED BY SINGLECELL
RNA SEQUENCING
Shirin Nkongolo1, Deeqa Mahamed1,2, Sam Kim3, Aman
Mehrotra1, Anjali Patel1, Diana Chen3,4, Jordan J. Feld5, Scott
K. Fung6, Jeffrey Wallin3, Anuj Gaggar3, Harry L.A. Janssen7
and Adam J. Gehring6,8, (1)Toronto Centre for Liver Disease,
Toronto General Hospital Research Institute, University
Health Network, (2)Centre for Advanced Single Cell Analysis,
the Hospital for Sick Children, Toronto, (3)Gilead Sciences
Inc., Foster City, California, USA, (4)Gilead Sciences, Inc.,
Foster City, CA, USA, (5)Toronto Centre for Liver Disease/
Viral Hepatitis Care Network (VIRCAN), University Health
Network, (6)Toronto Centre for Liver Disease, University
Health Network, (7)Toronto Centre for Liver Disease, Toronto
General Hospital, University Health Network, (8)Department
of Immunology, University of Toronto
Background: Liver damage during chronic Hepatitis B
virus (HBV) infection is caused by liver-infiltrating, activated
immune cells driving non-specific hepatocyte cell death.
Liver damage is defined clinically by elevated alanine
aminotransferase (ALT) in the serum Nucleoside analogue
therapy reduces HBV replication and normalizes ALT but
how ALT normalization corresponds to intrahepatic immune
activation in chronic hepatitis B (CHB) patients is unknown
Methods: Fifteen CHB patients with active hepatitis were
enrolled in this investigator-initiated, prospective study to
investigate the effects of antiviral therapy on the activation
state of intrahepatic immunity We collected blood and liver
fine-needle aspiration (FNA) samples at baseline and 12
weeks after starting tenofovir alafenamide (TAF) treatment
Blood was subjected to analysis of virological markers,
hematology and clinical chemistry Longitudinal liver FNAs
from five patients were analyzed by single-cell RNA sequencing
(scRNAseq) Results: In the five patients with scRNAseq
data, mean baseline ALT was 7 1xULN (range 1 1-18 7xULN)
and mean HBV DNA at screening was 1 7x107 IU/ml (range
7 5x105-5 4x107 IU/ml) Serum ALT levels decreased up to 20-
fold and normalized in two of these five patients 12 weeks
after starting therapy HBV DNA decreased up to 5 Log10 but
remained detectable in all patients ScRNAseq of liver FNAs at
baseline displayed an anticipated activated immune signature
with expression of CD38, HLA-DR, CD137 and IFN-gamma
on CD8 T cells and MHC-II, CD74, SERPING1 and STAT1
on macrophages Despite a maximum of 20-fold decrease
in ALT at week 12 of treatment, transcriptional changes
in immune cells were minor We observed less than 3-fold
change in CD74 in macrophages (adjusted p value = 7 1x10-9)
and less than 2-fold change of key inflammatory genes such
as IFN-gamma in CD8 T cells (adjusted p value = 3 4x10-9)
Pathway analysis of NK cells and CD8 T cells, which mediate
liver damage, showed no significant changes in inflammatory
pathways at week 12 Flow cytometry validation for activation
marker expression is in progress Conclusion: Contrary to
expectations, ALT decreased without a corresponding distinct
decline in the activation state of intrahepatic immune cells
This indicates that intrahepatic immune activation may not be
solely responsible for liver damage Separating mechanisms
of immune activation and liver damage could have important
implications for immunotherapy. |
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发表于 2020-11-1 09:46