Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

Ha, Sang‐Jun; Jeon, Bo Young; Kim, S. C.; Kim, D. J.; Song, Mi-Young; Sung, Young Chul; Cho, Sang Nae

doi:10.1038/sj.gt.3302057

Cited by 64 publications

(61 citation statements)

References 43 publications

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“…17 In addition, we recently demonstrated that Ag85A DNA vaccine, when simultaneously treated with chemotherapy, could be effective in preventing reactivation of aerogenically infected M. tuberculosis. 18 In contrast, Hsp60 or Ag85A DNA vaccines, which were administered after chemotherapy, had no effect. 15 The discrepancy may be caused by differences in the route of infection (aerosol versus intravenous), antigens used in each vaccine, strain and dose of infected bacteria, and the regimen of antibacterial drug treatment.…”

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“…: cytomegalovirus immediate-early enhancer/promoter; TPL: adenovirus tripartite leader sequence; MCS: multicloning site. (b) Each group of 6-weekold C57BL/6J mice was given aerogenic infection with 50 Â CFU of M. tuberculosis H37Rv as described previously 18 and maintained under barrier conditions in a BL-3 biohazard animal room. At 4 weeks after postinfection, the infected mice were treated with INH and PZA in diet for a period of 12 weeks as described previously.…”

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“…At 4 weeks after postinfection, the infected mice were treated with INH and PZA in diet for a period of 12 weeks as described previously. 18 During chemotherapy, total 40 mg of the following plasmid DNA was intramuscularly administered to each group of mice five times at the indicated weeks. Gr1, pGX10 (40 mg); Gr2, pGX10-Ag85A (20 mg)+pGX10 (20 mg); Gr3, pGX10-PstS-3 (20 mg)+pGX10 (20 mg); Gr4, pGX10-Ag85A (20 mg)+pGX10-PstS-3 (20 mg).…”

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“…(c) At specific time points up to 54 weeks postinfection, the number of viable bacilli in the lungs of Gr1 (~) and Gr2-Gr4 mice (}) was determined by plating lung homogenates and enumerating CFU to estimate reactivation of bacteria as described. 18 The CFU of Gr1 mice at 54 weeks is the average value from the lungs of reactivated mice only. Data are expressed as means7s.e.m.…”

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confidence: 99%

“…This result agrees well with the previous reports that the CpG motifs in the empty DNA vaccine may play a role in inducing Ag85A-specific Th1 immune responses. 18 DNA immunization of Ag85A DNA (Gr2) or PstS-3 DNA (Gr3) during chemotherapy could induce strong Ag85A-or PstS-3-specific IFN-g responses. IFN-g responses specific for CFP were higher in Gr2 than in Gr3, because Ag85A protein is the major protein component of M. tuberculosis CFP.…”

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Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

Jeon

Youn

et al. 2005

Gene Ther

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Active disease of tuberculosis (TB) can be developed decades later by either a relapse of the initial infection (endogenous reactivation) or by an entrance of the secondary infection (exogenous reinfection), since the current chemotherapy cannot lead to complete elimination of tuberculosis. Although the immunotherapeutic approaches in conjunction with conventional chemotherapy were tried to prevent TB growth via boosting the immune system, their therapeutic effects are still controversial. Here, we found that TB DNA vaccination completely blocked tuberculosis reactivation and significantly prevented from the secondary infection when chemotherapy was combined simultaneously.In particular, double-gene DNA vaccine composed of Ag85A and PstS-3 genes could reduce bacteria growth better than single-gene DNA vaccine after a secondary reinfection, indicating a correlation between the breadth of Th1 IFN-g response and the efficacy of the protection from reinfection. Thus, we propose that multigene TB DNA immunotherapy including Ag85A and PstS-3 genes during the period of chemotherapy could benefit patients undergoing TB chemotherapy in prevention from exogenous reinfection as well as endogenous reactivation. Gene Therapy (2005) Tuberculosis (TB) holds the dubious honor of being the leading single-agent infectious disease killer in the world 1,2 and the situation is worsened by the increasing incidence of both multidrug resistant (MDR) stains and combination with AIDS. 1,3 After Mycobacterium tuberculosis infection, active disease arises in about 5% of exposed individuals and most of the others will develop a latent infection in which the tubercle bacilli can persist in vivo without causing any clinical symptoms. However, active disease may also develop decades later either as a relapse of the initial infection or because of a secondary infection. Although most cases of tuberculosis were once believed to result from a endogenous reactivation acquired in the past, 4 recent studies indicate that onethird of tuberculosis cases are due to recent transmission by exogenous reinfection of multiple M. tuberculosis strains, [5][6][7][8][9] implicating that the exogenous reinfection significantly contributes to disease transmission. Therefore, novel immunotherapeutic approaches will be required to prevent reinfection as well as reactivation of M. tuberculosis in individuals with latent tuberculosis.DNA vaccination has become a promising strategy for developing an effective vaccine against TB, since it efficiently induces Th1 immunity, an essential arm of immune system to clear the bacteria. In prophylactic settings, there are several reports that DNA vaccines expressing M. tuberculosis antigens are effective for limiting the bacterial growth in mice. 10-13 However, it is still controversial whether DNA vaccines work against TB reactivation in postexposure models. 14-16 For example, the vaccination of plasmid DNA expressing hsp65 after completion of chemotherapy was shown to be effective in preventing the reactivation of intravenou...

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Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

Jeon

Youn

et al. 2005

Gene Ther

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PlasmidDNAand MessengerRNAfor Therapy

Pascolo

2010

Pharmaceutical Sciences Encyclopedia

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Recent studies performed in animal models and humans show that injection of pDNA or mRNA is safe and can elicit the expected results. Because pDNA and stabilized mRNA have the natural capacity to activate the immune system through the triggering of TLR, pDNA‐ and mRNA‐based therapeutic utilizations are mostly tested in the field of vaccination. This article focuses on therapeutic applications of pDNA‐ and mRNA‐based approaches.

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Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

et al. 2010

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IL-7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc-fused IL-7 (IL-7-Fc m ) as a genetic adjuvant significantly enhanced not only CD4 1 but also CD8 1 T-cell responses by E7 DNA immunization, in addition to improving protection against TC-1-induced tumors in comparison to IL-7 alone. Similar results were obtained in OT-1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8 1 T cells was mainly due to enhanced T-cell proliferation in T-cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co-delivery of lytic Fc-fused IL-7 (IL-7-Fc) which increases T-cell apoptosis as well as T-cell proliferation, suggesting that the T-cell proliferative effect may be neutralized by T-cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4 1 and CD8 1 T-cell responses.

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Therapeutic effect of DNA vaccines combined with chemotherapy in a latent infection model after aerosol infection of mice with Mycobacterium tuberculosis

Cited by 64 publications

References 43 publications

Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

Protective effect of DNA vaccine during chemotherapy on reactivation and reinfection of Mycobacterium tuberculosis

PlasmidDNAand MessengerRNAfor Therapy

Marked enhancement of antigen‐specific T‐cell responses by IL‐7‐fused nonlytic, but not lytic, Fc as a genetic adjuvant

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