T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay?

Rm, Zinkernagel; Haenseler, E; Leist, Th.; Cerny, Andreas; Hengartner, Hans; Althage, Alana

doi:10.1084/jem.164.4.1075

Cited by 203 publications

(166 citation statements)

References 45 publications

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“…non-lymphoid) organ. In animal models, most graphically in that of lymphocytic choriomeningitis virus in the mouse (LCMV), there is good experimental evidence that CTLs play a primary role in the immune control of acute infection, and also that they contribute to tissue damage, for example hepatic in£am-mation (Zinkernagel 1996;Zinkernagel et al 1986). In human infections such as human immunode¢ciency virus (HIV) and Epstein^Barr virus (EBV), large populations of these cells can be observed, and their emergence may be temporally linked to control of viraemia (Callan et al 1996(Callan et al , 1998Koup et al 1994).…”

Section: Introductionmentioning

confidence: 99%

Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Lechner

Sullivan

Spiegel

et al. 2000

Phil. Trans. R. Soc. Lond. B

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Hepatitis C virus (HCV) infection is a major public health problem, a¡ecting an estimated 3% of the world's population, and over 10% in some countries. Infection in most cases becomes persistent, and can lead to hepatic in£ammation, ¢brosis and liver failure. The T lymphocyte reponse, in particular that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involved in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide tetrameric complexes (tetramers) to study antiviral CTL responses has revolutionized our approach to the study of human infection. We have used a panel of MHC class I tetramers to analyse immune responses in HCV-infected individuals at various stages of disease. We ¢nd that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms of lymphocyte number and function. A number of potential explanations for this`CTL failure' are discussed.

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Section: Introductionmentioning

confidence: 99%

Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Lechner

Sullivan

Spiegel

et al. 2000

Phil. Trans. R. Soc. Lond. B

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“…However, in the event of viral persistence, exaggerated and prolonged T cell activation results in severe liver pathology which can eventually be fatal. 2,3 Thus CD8…”

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confidence: 99%

Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice

et al. 2010

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The innate immune response plays an essential role in the prevention of early viral dissemination. We used the lymphocytic choriomeningitis virus model system to analyze the role of tissue macrophages/Kupffer cells in this process. Our findings demonstrated that Kupffer cells are essential for the efficient capture of infectious virus and for preventing viral replication. The latter process involved activation of Kupffer cells by interferon (IFN)-I and prevented viral spread to neighboring hepatocytes. In the absence of Kupffer cells, hepatocytes were not able to suppress virus replication, even in the presence of IFN-I, leading to prolonged viral replication and severe T cell-dependent immunopathology. Conclusion: Tissue-resident macrophages play a crucial role in early viral capture and represent the major liver cell type exhibiting responsiveness to IFN-I and providing control of viral replication. (HEPATOLOGY 2010;52:25-32) P ersistent infection with hepatitis B or hepatitis C virus is one of the leading causes of lethal liver disease resulting from the development of liver cirrhosis and/or hepatocellular cancer.1 Because both viruses are poorly cytopathic, most of the ensuing liver destruction results from CD8 þ T cell responses directed against virus-infected hepatocytes. These cells prevent rapid dissemination of the virus and control viral replication by secreting interferon (IFN)-c and perforin. However, in the event of viral persistence, exaggerated and prolonged T cell activation results in severe liver pathology which can eventually be fatal. 2,3Thus CD8 þ T cells play a crucial role in both virus control and immunopathology. [4][5][6][7][8] Macrophages are resident in every organ of the body.9-11 With their potent phagocytic capacity, theyAbbreviations: ALT, alanine aminotransferase; IFN, interferon; IFNAR, IFN-a receptor; LCMV, lymphocytic choriomeningitis virus; LCMV-NP, lymphocytic choriomeningitis virus nucleoprotein.From the

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“…Primary ex vivo and secondary 51 Cr-release assays after 5 days of in vitro restimulation have been described earlier. 25 …”

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confidence: 99%

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

Mumprecht

Matter

Pavelic

et al. 2006

Blood

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IntroductionImatinib mesylate (STI571, Glivec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases (TKs) ABL, BCR/ABL, ARG, PDGF-R ␣ and ␤, and c-KIT. Constitutive activation of these TKs has been documented in chronic myeloid leukemia (CML), Philadelphia chromosome-positive (Ph ϩ ) acute lymphocytic leukemia, myeloproliferative disorders due to chromosomal rearrangements in PDGF-R, and gastrointestinal stromal tumors with mutations in c-KIT. [1][2][3][4] In these diseases, blocking of TKs with imatinib is very efficient and substantially improves clinical outcome.Since TKs are involved in various intracellular signaling pathways, it is not surprising that imatinib treatment affects immune responses. Clinical observations have suggested that imatinib treatment correlates with a reversible dose-dependent lymphopenia and hypogammaglobulinemia. 5 Experimental in vitro studies have demonstrated that imatinib inhibited the development of human CD34 ϩ progenitor cell-derived dendritic cells (DCs). In addition, DCs exposed to imatinib were less potent in inducing cytotoxic T-cell (CTL) responses against tumor and recall antigens. 6 However, results of the effect of imatinib on DC maturation are controversial. Other experiments have suggested a normal maturation but reduced expansion of DCs in mice when stimulated with Flt3L. 7 Further, it has been shown that treating DCs in vitro with imatinib enhanced antigen-presenting cell function and overcame tumor-induced CD4 ϩ T-cell tolerance. 8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process. TCR ligation triggers a signaling cascade that includes activation of the TKs Lck, ZAP70, and Ltk. A recent study has reported the requirement of c-ABL and ARG TKs for TCR-dependent transcriptional activation. 11 c-ABL is activated by Lck and then leads to the phosphorylation of ZAP70. It remains unclear whether c-ABL activates only ZAP70 or also activates other downstream proteins. 12 However, primary T cells lacking functional ABL TKs showed decreased IL-2 production and cell proliferation in response to TCR stimulation. 11 Comparably, it has been shown that ABL phosphorylates the BCR coreceptor CD19, suggesting a role for ABL in the regulation of B-cell proliferation. 13 Taken together, these experiments suggest that imatinib treatment in vivo may crucially influence antiviral CD8 ϩ T-and B-cell responses. However, physiologic consequences of imatinib treatment on protective immune response have not yet been demonstrated.Primary infection with lymphocytic choriomeningitis virus (LCMV), a noncytopathic RNA virus, is controlled almost ex...

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T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the 51Cr-release assay?

Cited by 203 publications

References 45 publications

Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

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