CD154–CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis†

Zhou, Feng; Ajuebor, Maureen N.; Beck, Paul L.; Le, Tai; Hogaboam, Cory M.; Swain, Mark G.

doi:10.1002/hep.20802

Cited by 34 publications

(29 citation statements)

References 47 publications

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“…1 and 2), it was very surprising that singular or combined neutralization of IFN-g or TNF-a had no effect on the liver pathology of infected WSX-1 2/2 mice, although this is in agreement with a previous study where administration of anti-IFN-g did not affect the outcome of T. gondii infection (15). Alternatively, WSX-1 2/2 CD4 + T cells may mediate their damaging effects on hepatocytes directly via FAS-FAS ligand or CD154-CD40 interactions and/or by the production of proteases (39)(40)(41). Experiments are under way to test these hypotheses and to elucidate the IL-27-dependent pathways controlling migration to and accumulation of effector CD4 + T cells within the liver during malaria infection.…”

Section: Discussionsupporting

confidence: 90%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

110

123

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Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.

show abstract

Section: Discussionsupporting

confidence: 90%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

The Journal of Immunology

110

123

View full text Add to dashboard Cite

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“…Zhou and coworkers, 23 in a concanavalin A model, reported that the CD40L-CD40 interaction plays a major role in triggering hepatocellular apoptosis by demonstrating that hepatitis, tumor necrosis factor ␣ levels, and hepatocyte death was significantly attenuated in CD40L Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

et al. 2006

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Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 ؎ 279 U/L; AdLacZ, 213 ؎ 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40 -CD40L interaction was mandatory for liver damage, because CD40 ؊/؊ mice were completely protected. F ulminant hepatic failure (FHF) is a life-threatening condition induced by pathogens such as hepatitis B virus infection and drug toxicity. The underlying pathophysiological mechanisms are not fully understood. This renders a causal therapeutic approach difficult. 1,2 Uncontrolled hepatic immunoactivation is discussed as a pivotal pathomechanism of FHF. 3-5 Recently, we described significant intrahepatic upregulation of the immunoactivating molecules CD40 and its ligand (CD40L/ CD154) in patients with FHF. 3 In human FHF, CD40 was upregulated in hepatocytes, sinusoidal and vascular endothelial cells, and macrophages/Kupffer cells, whereas CD40L was expressed in an increased number of intrahepatic lymphocytes. Taking into account our observation of strongly enhanced hepatic CD40 and CD40L expression in FHF and the potent immunoactivating properties of the CD40 -CD40L interaction, we hypothesized that the interaction of CD40 with CD40L is a pivotal trigger of immune cascade-inducing FHF.CD40L is a member of the tumor necrosis factor receptor superfamily and is expressed on activated CD4 ϩ T cells and platelets. 6,7 The CD40 -CD40L interaction induces strong immunoactivation at different levels of the immune system, including T cells, B cells, macrophages, and dendritic cells. Interaction of CD40 -CD40L on dendritic cells and other antigen-presenting cells such as monocytes/macrophages and B lymphocytes upregulates Abbreviations: FHF, fulminant hepatic failure; CD40L, CD40 ligand; AdCD40L, adenoviral CD40 ligand; ALT, alanine aminotransferase; NKT cell, natural killer T cell; pfu,

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“…Several human 2,4 and animal [24][25][26][27] studies using CD40 agonists report elevated levels of circulating hepatocyte enzymes ALT and AST, indicative of liver damage. To examine the severity of hepatocellular damage with monotherapy versus combination therapy, we measured plasma levels of ALT and AST in mice after vaccination ( Figure 5A,B).…”

Section: ␣Cd40-induced Hepatocellular Injury Is Reduced By Coadministmentioning

confidence: 99%

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

Ahonen

Wasiuk

Fuse

et al. 2008

Blood

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Identification of Toll-like receptors (TLRs)and their ligands, and tumor necrosis factor-tumor necrosis factor receptor (TNF-TNFR) pairs have provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants to elicit potent cell-mediated immunity via activation of innate and adaptive immunity. However, isolated activation of one immune pathway in the absence of others can be toxic, ineffective, and detrimental to long-term, protective immunity. Effective engineered vaccines must include agents that trigger multiple immunologic pathways. Here, we report that combinatorial use of CD40 and TLR agonists as a cancer vaccine, compared with monotherapy, elicits high frequencies of selfreactive CD8 ؉ T cells, potent tumorspecific CD8 ؉ memory, CD8 ؉ T cells that efficiently infiltrate the tumor-burdened target organ; therapeutic efficacy; heightened ratios of CD8 ؉ T cells to FoxP3 ؉ cells at the tumor site; and reduced hepatotoxicity. These findings provide intelligent strategies for the formulation of multifactorial vaccines to achieve maximal efficacy in cancer vaccine trials in hu IntroductionThe molecular identification of Toll-like receptors (TLRs) and their ligands, as well as tumor necrosis factor (TNF)-tumor necrosis factor receptor (TNFR) pairs that control adaptive immunity, has provided the first logical, hypothesis-based strategies to molecularly concoct adjuvants that elicit potent cell-mediated immunity. Paralleling TLRs in mobilizing the innate immune response, CD40 and its ligand represent the primary ligand-receptor pair essential for development of the adaptive immune response. Individually, TLR agonists 1 and CD40 agonists 2-4 have entered clinical trials as adjuvants for eliciting protective immune responses to cancer. Inherent in these monotherapeutic approaches are limited induction of immunity, lack of clinical efficacy and, in some cases, hepatotoxicity. 3,4 TLRs are widely expressed on both hematopoietic and nonhematopoietic cells and elicit proinflammatory responses upon receptor engagement. Indeed, use of TLR agonists as solitary adjuvants triggers dendritic cell (DC) maturation, leukocyte migration, and release of chemokines and cytokines, and enhances immunity. 5,6 Studies in which TLR agonists have been scrutinized for their ability to induce cross-presentation and antigen-specific CD8 ϩ responses in vivo 7 show some level of activity that is minimal compared with that observed when combined with a CD40 agonist. 8,9 TLR agonists as unitary adjuvants in murine tumor models have demonstrated marginal efficacy, as reviewed, 10 but have proven effective when combined with other vaccine modalities. [11][12][13] Finally, clinical use of a TLR9 agonist in lung cancer trials has been recently suspended due to lack of clinical response. 1Studies from animal models underscore the utility of anti-CD40 (␣CD40) as a unitary adjuvant. 14,15 We previously demonstrated that the magnitude of immune responses elicited by TLR or CD40 agonists alone is minimal compared with the magnit...

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CD154–CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis†

Cited by 34 publications

References 47 publications

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines

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