Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis

Descamps, Delphyne; Vigant, Frédéric; Esselin, Stéphanie; Connault, Elisabeth; Opolon, Paule; Perricaudet, Michel; Benihoud, Karim

doi:10.1002/hep.21257

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…Using experiments in mouse, we detected no liver damage after intravenous injection. Although these findings seem in contradiction with data showing that Fas engagement in mice induce an acute liver injury, it is noteworthy that these reports used in fact the anti-Fas JO2 agonistic antibody and not FasL [3], [29], [30], [31], [32]. The liver destruction observed following injection of anti-Fas antibodies may simply be the consequence of an antibody-dependent cell-mediated cytotoxicity reaction [33], as the production of inflammatory cytokines by Fc receptor–bearing Kupffer cells has been observed [34].…”

Section: Discussioncontrasting

confidence: 84%

Functional Characterization of a Chimeric Soluble Fas Ligand Polymer with In Vivo Anti-Tumor Activity

et al. 2013

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Binding of ligand FasL to its receptor Fas triggers apoptosis via the caspase cascade. FasL itself is homotrimeric, and a productive apoptotic signal requires that FasL be oligomerized beyond the homotrimeric state. We generated a series of FasL chimeras by fusing FasL to domains of the Leukemia Inhibitory Factor receptor gp190 which confer homotypic oligomerization, and analyzed the capacity of these soluble chimeras to trigger cell death. We observed that the most efficient FasL chimera, called pFasL, was also the most polymeric, as it reached the size of a dodecamer. Using a cellular model, we investigated the structure-function relationships of the FasL/Fas interactions for our chimeras, and we demonstrated that the Fas-mediated apoptotic signal did not solely rely on ligand-mediated receptor aggregation, but also required a conformational adaptation of the Fas receptor. When injected into mice, pFasL did not trigger liver injury at a dose which displayed anti-tumor activity in a model of human tumor transplanted to immunodeficient animals, suggesting a potential therapeutic use. Therefore, the optimization of the FasL conformation has to be considered for the development of efficient FasL-derived anti-cancer drugs targeting Fas.

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Section: Discussioncontrasting

confidence: 84%

Functional Characterization of a Chimeric Soluble Fas Ligand Polymer with In Vivo Anti-Tumor Activity

et al. 2013

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“…However, because neutralizing antibodies against death ligands or soluble death receptors exhibit a systemic action, they could modify the host's ability to respond to pathogens. A more appealing strategy to improve the therapeutic index of Ad gene therapy could be to specifically express into hepatocytes membrane decoy receptors of the TNFR family unable to trigger apoptotic signals [118]. This could be achieved by the use of tissue-specific and regulable promoters.…”

Section: Avoiding Elimination Of Transduced Hepatocytes By Innate Immmentioning

confidence: 99%

Two Key Challenges for Effective Adenovirus-Mediated Liver Gene Therapy:Innate Immune Responses and Hepatocyte-Specific Transduction

Descamps

Benihoud²

2009

CGT

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Adenovirus (Ad) are valuable vectors for liver gene therapy because of their intrinsic ability to transduce hepatocytes following intravenous administration. However, the effective application of these vectors, including helper-dependent Ad unable to trigger viral gene expression, for liver gene therapy in humans has been limited due to several obstacles. First, their high immunogenicity triggers a complex immune response, both innate and adaptive, that leads to hepatocyte destruction, reducing the duration of transgene expression. This high immunogenicity also induces a long lasting cellular and humoral immunity that impairs subsequent re-administration. Second, Ad vectors transduce not only hepatocytes but also other cell types from the liver or other organs. This Ad vector dissemination contributes to their toxicity and immunogenicity, further reducing the effective period of transgene expression. A better understanding of the interactions between Ad vectors and their host underlying the acute liver toxicity and hepatocyte transduction is required to improve the efficacy and duration of gene delivery in vivo. The aim of this review is to discuss insights into the cellular and molecular mechanisms involved in Ad vector-mediated innate immune responses. Current advances in the knowledge of Ad liver tropism and the influence of blood components on Ad vector uptake by the liver will be discussed. Finally, different approaches developed to minimize Ad vector toxicity, optimize delivery and increase transgene expression will be summarized. The full potential of Ad vectors will only be reached when their immunogenicity is abolished and hepatocyte-specific transduction achieved.

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“…We therefore analyzed the effect on tumor growth in CD5-deficient mice of an adenovirus encoding a murine sFas (AdmFas-Fc), previously described for its capacity to neutralize CD95L in vivo (29). For this purpose, we injected i.v.…”

Section: Suppression Of Fas-mediated Aicd Enhances the Antitumor Immumentioning

confidence: 99%

Rescue of Tumor-Infiltrating Lymphocytes from Activation-Induced Cell Death Enhances the Antitumor CTL Response in CD5-Deficient Mice

Tabbekh

Franciszkiewicz

Haouas

et al. 2011

The Journal of Immunology

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The CD5 coreceptor is expressed on all T cells and on the B1a B cell subset. It is associated with TCR and BCR, and modulates intracellular signals initiated by both Ag receptor complexes. Human CD5 contributes to regulation of the antitumor immune response and susceptibility of specific CTL to activation-induced cell death (AICD) triggered by the tumor. In this study, we compared the T cell response to the B16F10 melanoma engrafted into CD5-deficient and wild-type C57BL/6 mice. Compared with wild-type mice, CD5 knockout animals displayed delayed tumor growth, associated with tumor infiltration by T cell populations exhibiting a more activated phenotype and enhanced antitumor effector functions. However, control of tumor progression in CD5−/− mice was transient due to increased AICD of CD8+ tumor-infiltrating T lymphocytes. Remarkably, in vivo protection of T cells from TCR-mediated apoptosis by an adenovirus engineered to produce soluble Fas resulted in a dramatic reduction in tumor growth. Our data suggest that recruitment of tumor-specific T cells in the tumor microenvironment occurs at early stages of cancer development and that tumor-mediated AICD of tumor-infiltrating T lymphocytes is most likely involved in tumor escape from the immune system.

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Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis

Cited by 9 publications

References 48 publications

Functional Characterization of a Chimeric Soluble Fas Ligand Polymer with In Vivo Anti-Tumor Activity

Functional Characterization of a Chimeric Soluble Fas Ligand Polymer with In Vivo Anti-Tumor Activity

Two Key Challenges for Effective Adenovirus-Mediated Liver Gene Therapy:Innate Immune Responses and Hepatocyte-Specific Transduction

Rescue of Tumor-Infiltrating Lymphocytes from Activation-Induced Cell Death Enhances the Antitumor CTL Response in CD5-Deficient Mice

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