Hepatocytes as cytotoxic effector cells can induce cell death by CD95 ligand-mediated pathway

Guy, Clifford S.; Wang, Jinguo; Michalak, Tomasz I.

doi:10.1002/hep.21201

Cited by 28 publications

(58 citation statements)

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“…On the other hand, this peak of CD95L expression occurred together with the upregulated transcription of CD3, suggesting a possible contribution of NKT cells to the increased intrahepatic detection of CD95L. However, we have previously reported that hepatocytes also constitutively express CD95L (18). Thus, it cannot be completely excluded that an increase in the intrahepatic CD95L mRNA level was due at least in part to the elevated transcription of CD95L in hepatocytes.…”

Section: Intrahepatic Cd4mentioning

confidence: 73%

“…Total RNA was isolated from liver biopsy samples using Trizol reagent (Invitrogen Life Technologies, Burlington, Ontario, Canada), as per the manufacturer's instruction. RNA was treated with DNase to remove potentially contaminating DNA using an RNase-free DNase digestion kit (Sigma Chemical Company, Oakville, Ontario, Canada) prior to reverse transcription to cDNA, as previously described (18).…”

Section: Methodsmentioning

confidence: 99%

“…To facilitate analysis of the spectrum and the dynamics of intrahepatic immune response in WHV infection, a number of woodchuck gene sequences encoding markers specifying different immune cell subtypes, immune cell effector molecules, and cytokines were determined, applying a strategy previously reported (18). In general, woodchuck gene sequences were identified by reverse transcription-PCR (RT-PCR) using degenerate oligonucleotide primers whose sequences were deduced through interspecies comparison of the sequences available in GenBank.…”

Section: Methodsmentioning

confidence: 99%

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Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus

Guy¹,

Mulrooney‐Cousins²,

Churchill³

et al. 2008

J Virol

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The importance of effective immune responses in recovery from acute hepadnaviral hepatitis has been demonstrated. However, there is no conclusive delineation of virological and immunological events occurring in the liver immediately after hepadnavirus invasion and during the preacute phase of infection. These very early events might be of primary importance in determining the recovery or progression to chronic hepatitis and the intrinsic hepadnaviral propensity to persist. In this study, applying the woodchuck model of acute hepatitis B, the hepatic kinetics of hepadnavirus replication and activation of genes encoding cytokines, cytotoxicity effectors, and immune cell markers were quantified in sequential liver biopsies collected from 1 h postinoculation onward by sensitive real-time cDNA amplification assays. The results revealed that hepadnavirus replication is established in the liver as early as 1 hour after infection. In 3 to 6 h, significantly augmented intrahepatic transcription of gamma interferon and interleukin-12 were evident, suggesting activation of antigen-presenting cells. In 48 to 72 h, NK and NKT cells were activated and virus replication was transiently but significantly reduced, implying that this early innate response is at least partially successful in limiting virus propagation. Nonetheless, T cells were activated 4 to 5 weeks later when hepatitis became histologically evident. Collectively, our data demonstrate that virus replication is initiated and the innate response activated in the liver soon after exposure to a liver-pathogenic dose of hepadnavirus. Nevertheless, this response is unable to prompt a timely adaptive T-cell response, in contrast to infections caused by other viral pathogens.

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Section: Intrahepatic Cd4mentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus

Guy¹,

Mulrooney‐Cousins²,

Churchill³

et al. 2008

J Virol

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“…For the evaluation of messenger ribonucleic acid (mRNAs) of TLR3, RIG-I, MDA-5, PKR, NF-B, interferon regulatory factor-3 (IRF-3), IFN-␤, MxA, TRAIL, TRAIL receptors (TRAIL-DR4, TRAIL-DR5, TRAIL-DcR1, and TRAIL-DcR2), CD95, and CD95 ligand in cultured BECs, total RNA was isolated from BECs, and 1 g total RNA was reverse-transcribed with an oligo-(dT) primer and reverse transcriptase to synthesize complementary deoxyribonucleic acid. Human cultured cell lines (HuCCT1, HuH7, HepG2, and WI38) and normal tissues (pancreas and liver) [18][19][20][21][22][23][24][25][26][27] were used as controls, and the complementary deoxyribonucleic acid was amplified by polymerase chain reaction (PCR) using the specific primers ( Table 1). The PCR products were subjected to electrophoresis on 1.5% agarose gels containing ethidium bromide.…”

Section: Patients and Tissue Preparationsmentioning

confidence: 99%

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

et al. 2007

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B iliary atresia (BA) is characterized by a progressive, inflammatory, and sclerosing cholangiopathy. Little is known about the etiology and pathogenesis of BA, but recent studies have demonstrated the presence of Reoviridae (type 3 reovirus and type C rotavirus) having a double-strand RNA (dsRNA) in liver tissue of patients with BA, although conflicting results have been reported. [1][2][3][4][5] Moreover, the infection of newborn Balb/cmice with Reoviridae including type A rhesus rotavirus and type 3 reovirus (Abney) leads to cholestasis and biliary obstruction resembling human BA. 6,7 However, the role of these viruses in the pathogenesis of cholangiopathies in patients with BA is still unknown.Toll-like receptors (TLRs) are innate immune-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs), and TLR3 recognizes dsRNA including dsRNA viruses. 8 The stimulation of TLR3 by dsRNA transduces signals to activate the transcription factors nuclear factor-B (NF-B) and interferon regulatory factor 3 (IRF3) via Toll-interleukin-1 receptor do-

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“…Peptides were synthesized by Proimmune (Oxford University, UK). HBV-core [18][19][20][21][22][23][24][25][26][27] , an HLA-A*0201-restricted cytotoxic T lymphocyte epitope of HBV core protein, 12 was used as a control peptide. All peptides were constructed with free NH 2 -termini and COOH-termini and their purity was Ͼ90% as determined via analytical reverse-phase HPLC.…”

Section: Methodsmentioning

confidence: 99%

Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2

et al. 2007

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Autoimmune hepatitis type 2 (AIH-2) is a severe organ-specific disorder characterized by liver kidney microsomal antibody type 1 targeting cytochrome P4502D6 (CYP2D6). Growing evidence implicates the involvement of CD8 T cell immune responses in its pathogenesis. We investigated CYP2D6-specific CD8 T cell human leukocyte antigen (HLA)-A2 restricted responses in AIH-2 (20 patients, 11 HLA-A2؉). Binding affinity of CYP2D6 peptides to HLA-A2 was predicted by the algorithm SYFPEITHI and assessed in vivo by T2 cell assays. CD8 T cell interferon (IFN)-␥ production was assessed via intracellular cytokine staining, cytotoxicity via chromium release assay, and frequency of circulating and intrahepatic CYP2D6-specific CD8 T cells via tetramer staining. CYP2D6-specific CD8 T cell reactivity was tested at diagnosis and during treatment and correlated with indices of disease activity. Seven CYP2D6 peptides with high HLA-A2 binding affinity colocalizing with known B cell or CD4 T cell epitopes were selected. Five sequences inducing high levels of IFN-␥ were used for HLA-A2 tetramer construction. Frequency, IFN-␥ production, and cytotoxicity of CYP2D6-specific CD8 T cells were higher at diagnosis than during treatment. Intensity of CYP2D6-specific CD8 T cell responses correlated with disease activity. Immune responses to CYP2D6 245-254 were the strongest both at diagnosis and during treatment. Conclusion: HLA-A2-restricted, CYP2D6-specific CD8 T cell immune responses vary according to disease stage and correlate with hepatocyte damage. CD8 T cell targets on CYP2D6 -in particular CYP2D6 245-254 -may be the focus of novel immune intervention in AIH-2. (HEPATOLOGY 2007;46:472-484.)

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Hepatocytes as cytotoxic effector cells can induce cell death by CD95 ligand-mediated pathway

Cited by 28 publications

References 50 publications

Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus

Intrahepatic Expression of Genes Affiliated with Innate and Adaptive Immune Responses Immediately after Invasion and during Acute Infection with Woodchuck Hepadnavirus

Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia

Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2

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