Targeted induction of antigen expression within dendritic cells modulates antigen-specific immunity afforded by recombinant BCG

Kong, Carlyn U.; Ng, Lai Guan; Nambiar, Jonathan K.; Spratt, Joanne M.; Weninger, Wolfgang; Triccas, James A.

doi:10.1016/j.vaccine.2010.12.070

Cited by 14 publications

(6 citation statements)

References 28 publications

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“…This theory was also corroborated by Kong et al (38) who constructed an rBCG expressing Mtb Ag85B under the control of a HspX promoter. The expression and immune response to Ag85B was modulated by the HspX promoter.…”

Section: Does the Quantity Of Mtb Antigens Incorporated In Bcg Resultsupporting

confidence: 59%

“…Despite the intense induction of immune cell responses, the protection in lungs and spleen induced by this vaccine was similar to that by BCG. This indicated that in a model of Ag85B expression under control of a different promoter, there was no improvement in protective efficacy (38). Although Ag85C is responsible for more than 40% of the mycolate present in the mycobacteria cell wall (61), evidence suggests that Ag85B is critical for enhanced BCG induction of memory and protection (49, 50).…”

Section: Does the Quantity Of Mtb Antigens Incorporated In Bcg Resultmentioning

confidence: 99%

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Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory

et al. 2014

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Bacille Calmette–Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory.

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Section: Does the Quantity Of Mtb Antigens Incorporated In Bcg Resultsupporting

confidence: 59%

Section: Does the Quantity Of Mtb Antigens Incorporated In Bcg Resultmentioning

confidence: 99%

Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory

et al. 2014

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“…The central cell that regulates this host response is the dendritic cell, and consequently it is increasingly viewed as a target for new therapeutic and vaccine strategies [19,68]. It is hoped that our description of the DC death response to Mtb infection - as pro-inflammatory, and without the activation of caspases - will inform further research that defines the T cell consequences of this innate response.…”

Section: Discussionmentioning

confidence: 99%

“…The impact of Mtb infection on DC survival, however, is poorly understood. Given the non-redundant role of DCs in mycobacterial immunity [9], and their identification as a target for novel therapies and vaccines [4,16-19], we sought to define the requirements and mechanism of DC cell death after infection with Mtb. By modelling human monocyte-derived DCs in vitro , we infected DCs with Mtb to assess phagocyte survival, and attendant caspase activity, cytokine production and mycobactericidal effect.…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

2011

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BackgroundDendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4+ and CD8+ T cell response after infection with Mycobacterium tuberculosis (Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival.ResultsInfection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth.ConclusionsHuman DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.

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“…Recombinant BCG is a satisfactory approach for obtaining better TB vaccines. The protective efficacy of BCG can be improved through recombinant BCG technology by insertion of immunodominant antigens such as ESAT-6, Ag85A, Ag85B, PPE protein, MPT64 and TB10.4 [8][9][10][11] and immunoregulatory cytokines such as IFN-c, IL-12, GM-CSF, IL-2, and IL-18 [12][13][14][15], etc. By rBCG technology, both the proteins secreted by BCG and recombinant proteins introduced to BCG can simultaneously stimulate the body to generate stronger immune responses to M. tuberculosis infection.…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity and Protective Efficacy Conferred by a Novel Recombinant Mycobacterium bovis Bacillus Calmette‐Guérin Strain Expressing Interleukin‐12p70 of Human Cytokine and Ag85A of Mycobacterium tuberculosis Fusion Protein

Deng

Zhang

2013

Scand J Immunol

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Mycobacterium bovis bacillus Calmette-Gu erin (BCG) immunization provides protection against tuberculosis (TB) in infants, but the antituberculosis protective immunity wanes gradually after initial immunization and lasts less than 15 years. Therefore, more efficacious vaccines are urgently needed. In this study, we constructed a new tuberculosis vaccine of recombinant BCG strain (rBCG-IA), which could express IL-12p70 of human cytokine and Ag85A of M. tuberculosis fusion protein, and investigated its immunogenicity in BALB/c mice by measuring antibody titres, proliferation rate of splenocytes, ratios of CD4 + T and CD8 + T cells stimulated by specific antigens and levels of IFN-c production in antigen-stimulated splenocyte cultures. Meanwhile, we evaluated its protective efficacy against M. tuberculosis H37Rv infection through detecting lung histopathology, organ bacterial loads and lung acid-fast stain. Immunogenicity experiments illustrated that from 2nd to 8th week after immunization, the rBCG-IA vaccine was able to induce the highest level of antibody titres, proliferation rate of splenocytes and IFN-c production among groups and gained improved ratio of CD4 + T and CD8 + T cells from 6th to 8th week after vaccination. And from 2nd to 8th week after M. tuberculosis H37Rv infection, the score of pathology and bacterial loads in the rBCG-IA group were obviously lower than that in rBCG-I group, rBCG-A group or control group (PBST group), but similar to that in BCG group. This study suggested that rBCG-IA was able to elicit stronger humoral and cellular immune responses, but could only confer similar protective efficacy compared with its parental BCG vaccine.

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Targeted induction of antigen expression within dendritic cells modulates antigen-specific immunity afforded by recombinant BCG

Cited by 14 publications

References 28 publications

Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory

Recombinant BCG: innovations on an old vaccine. Scope of BCG strains and strategies to improve long-lasting memory

Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

Immunogenicity and Protective Efficacy Conferred by a Novel Recombinant Mycobacterium bovis Bacillus Calmette‐Guérin Strain Expressing Interleukin‐12p70 of Human Cytokine and Ag85A of Mycobacterium tuberculosis Fusion Protein

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