Dendritic Cells and Damage-Associated Molecular Patterns: Endogenous Danger Signals Linking Innate and Adaptive Immunity

Nace, Gary W.; Evankovich, John; Eid, Raymond E.; Tsung, Allan

doi:10.1159/000334245

Cited by 122 publications

(95 citation statements)

References 185 publications

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“…In this process, DCs are largely influenced by the preceding innate immune response (36,37). Impairment of DC maturation and function by HHV-6-specific Treg cells not only suppresses innate immunity but also influences the adaptive immune response to HHV-6 infection (38). Our studies clearly suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape antivirus immune responses and maintain latency and immunosuppression in infected hosts.…”

Section: Discussionmentioning

confidence: 72%

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Wang

Chi

Peng

et al. 2014

J Virol

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؉ effector T cell immune responses but also could impair dendritic cell (DC) maturation and functions. In addition, the suppressive effects mediated by HHV-6-specific Treg cells were mainly through a cell-to-cell contact-dependent mechanism but not through the identified cytokines. These results suggest that HHV-6 may utilize the induction of Treg cells as a strategy to escape antivirus immune responses and maintain the latency and immunosuppression in infected hosts.

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Section: Discussionmentioning

confidence: 72%

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Wang

Chi

Peng

et al. 2014

J Virol

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“…Released DAMPs will be sensed by immune cells, most importantly dendritic cells (DCs) (59), which will endocytose the HCV antigens that are then cross-presented via a nonclassical pathway (60).…”

Section: Discussionmentioning

confidence: 99%

A Multiantigenic DNA Vaccine That Induces Broad Hepatitis C Virus-Specific T-Cell Responses in Mice

Gummow

et al. 2015

J Virol

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There are 3 to 4 million new hepatitis C virus (HCV) infections annually around the world, but no vaccine is available. Robust T-cell mediated responses are necessary for effective clearance of the virus, and DNA vaccines result in a cell-mediated bias. Adjuvants are often required for effective vaccination, but during natural lytic viral infections damage-associated molecular patterns (DAMPs) are released, which act as natural adjuvants. Hence, a vaccine that induces cell necrosis and releases DAMPs will result in cell-mediated immunity (CMI), similar to that resulting from natural lytic viral infection. We have generated a DNA vaccine with the ability to elicit strong CMI against the HCV nonstructural (NS) proteins (3, 4A, 4B, and 5B) by encoding a cytolytic protein, perforin (PRF), and the antigens on a single plasmid. We examined the efficacy of the vaccines in C57BL/6 mice, as determined by gamma interferon enzyme-linked immunosorbent spot assay, cell proliferation studies, and intracellular cytokine production. Initially, we showed that encoding the NS4A protein in a vaccine which encoded only NS3 reduced the immunogenicity of NS3, whereas including PRF increased NS3 immunogenicity. In contrast, the inclusion of NS4A increased the immunogenicity of the NS3, NS4B, andNS5B proteins, when encoded in a DNA vaccine that also encoded PRF. Finally, vaccines that also encoded PRF elicited similar levels of CMI against each protein after vaccination with DNA encoding NS3, NS4A, NS4B, and NS5B compared to mice vaccinated with DNA encoding only NS3 or NS4B/5B. Thus, we have developed a promising "multiantigen" vaccine that elicits robust CMI. IMPORTANCESince their development, vaccines have reduced the global burden of disease. One strategy for vaccine development is to use commercially viable DNA technology, which has the potential to generate robust immune responses. Hepatitis C virus causes chronic liver infection and is a leading cause of liver cancer. To date, no vaccine is currently available, and treatment is costly and often results in side effects, limiting the number of patients who are treated. Despite recent advances in treatment, prevention remains the key to efficient control and elimination of this virus. Here, we describe a novel DNA vaccine against hepatitis C virus that is capable of inducing robust cell-mediated immune responses in mice and is a promising vaccine candidate for humans. G lobal efforts to generate an effective vaccine for hepatitis C virus (HCV) have been hampered, since correlates of sterilizing immunity have not been identified and traditional vaccine strategies have proved to be ineffective (1). Approximately 230 million individuals are infected, many of whom will develop serious liver disease, and since current treatment is costly and often results in serious side effects, this has limited the number of patients who are treated (2, 3). Much of the global effort to develop an effective HCV vaccine/treatment has been directed toward genotype 1 (gt1) (4, 5); however, gt3 is ...

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“…Through experiments performed in vivo and in vitro, DAMPs induced by chemical drugs have been demonstrated to stimulate dendritic cells (DCs) to induce an anti-cancer immune response. [3][4][5] However, DAMPs also play a putative role in the promotion of tumor progression by attracting immature myeloid cells and triggering tumor cell proliferation. [6][7][8] Thus, how to more efficiently trigger an anti-cancer immune response mediated by DAMPs is worthy of attention.…”

Section: Introductionmentioning

confidence: 99%

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

et al. 2013

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The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns (DAMPs) can activate immune cells, including dendritic cells (DCs), via Toll-like receptors (TLRs); however, the role of DAMPs released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer (CRC) cells treated with oxaliplatin (OXA) and/or 5-fluorouracil (5-Fu) released high levels of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known DAMPs. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-1b, TNF-a, MIP-1a, MIP-1b, RANTES and IP-10 production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-c-producing Th1 response both in vitro and in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-c-producing Th1 response in TLR4-deficient DCs. Collectively, these results demonstrate that DAMPs released from chemically stressed cancer cells can activate DCs via TLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by DAMPs.

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Dendritic Cells and Damage-Associated Molecular Patterns: Endogenous Danger Signals Linking Innate and Adaptive Immunity

Cited by 122 publications

References 185 publications

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

A Multiantigenic DNA Vaccine That Induces Broad Hepatitis C Virus-Specific T-Cell Responses in Mice

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

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Dendritic Cells and Damage-Associated Molecular Patterns: Endogenous Danger Signals Linking Innate and Adaptive Immunity

Cited by 122 publications

References 185 publications

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

A Multiantigenic DNA Vaccine That Induces Broad Hepatitis C Virus-Specific T-Cell Responses in Mice

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

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Product

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Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection

Development of Virus-Specific CD4 ⁺ and CD8 ⁺ Regulatory T Cells Induced by Human Herpesvirus 6 Infection