Specificity and efficacy of dendritic cell-based vaccination against tuberculosis with complex mycobacterial antigens in a mouse model

Rubakova, Elvira I.; Petrovskaya, Svetlana; Pichugin, Alexander; Khlebnikov, V. S.; McMurray, David N.; Kondratieva, Elena; Батурина, И. Л.; Kondratieva, Tatiana; Apt, Alexander S.

doi:10.1016/j.tube.2006.06.002

Cited by 12 publications

(11 citation statements)

References 42 publications

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“…DCs play a crucial role in effective activation of T cells and induction of memory T-cell responses. It is reported that mice vaccinated with Mtb-infected DCs [29] or Mtb sonicate-pulsed DCs [16] are protected against Mtb infection. These results support that activating DCs in vivo is crucial in the development of antimycobacterial vaccine [30].…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that a mycobacterial antigen that elicits effective host protective immunity via DC activation is a promising target for development of a TB vaccine. In fact, DCs infected with BCG or pulsed with Mtb antigens induce significant protection to a challenge with both moderate and high doses of virulent Mtb in a mouse model [15, 16]. Although several mycobacterial proteins that activate DCs to drive a Th1 immune response have been identified, little is known about their detailed antimycobacterial mechanism and about protective efficacy of the protein itself as a vaccine.…”

Section: Introductionmentioning

confidence: 99%

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Rv2299c, a novel dendritic cell-activating antigen ofMycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice

Choi

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et al. 2017

Oncotarget

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Understanding functional interactions between DCs and antigens is necessary for achieving an optimal and desired immune response during vaccine development. Here, we identified and characterized protein Rv2299c (heat-shock protein 90 family), which effectively induced DC maturation. The Rv2299c-maturated DCs showed increased expression of surface molecules and production of proinflammatory cytokines. Rv2299c induced these effects by binding to TLR4 and stimulating the downstream MyD88-, MAPK- and NF-κB-dependent signaling pathways. The Rv2299c-maturated DCs also showed an induced Th1 cell response with bactericidal activity and expansion of effector/memory T cells. The Rv2299c-ESAT-6 fused protein had greater immunoreactivity than ESAT-6. Furthermore, boosting BCG with the fused protein significantly reduced hypervirulent Mycobacterium tuberculosis HN878 burdens post-challenge. The pathological study of the lung from the challenged mice assured the efficacy of the fused protein. The fused protein boosting also induced Rv2299c-ESAT-6-specific multifunctional CD4+ T-cell response in the lungs of the challenged mice. Our findings suggest that Rv2299c is an excellent candidate for the rational design of an effective multiantigenic TB vaccine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rv2299c, a novel dendritic cell-activating antigen ofMycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice

Choi

Back

et al. 2017

Oncotarget

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“…Antigen pulsed DCs have been used to monitor immune responses during M. tb infection [49]. In a monkey model of tuberculosis, Marino et al [50] demonstrated the importance of early sensing of M. tb infection by DCs, their migration to the lymph nodes and T cell trafficking.…”

Section: Discussionmentioning

confidence: 99%

Protective Immunity to Mycobacterium tuberculosis Infection by Chemokine and Cytokine Conditioned CFP-10 Differentiated Dendritic Cells

et al. 2008

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BackgroundDendritic cells (DCs) play major roles in mediating immune responses to mycobacteria. A crucial aspect of this is the priming of T cells via chemokines and cytokines. In this study we investigated the roles of chemokines RANTES and IP-10 in regulating protective responses from Mycobacterium tuberculosis (M. tb) 10 kDa Culture Filtrate Protein-10 (CFP-10) differentiated DCs (CFP10-DCs).Methods and FindingsInfection of CFP10-DCs with mycobacteria down-modulated RANTES and IP-10 levels. Pathway specific microarray analyses showed that in addition to RANTES and IP-10, mycobacteria infected CFP10-DCs showed reduced expression of many Th1 promoting chemokines and chemokine receptors. Importantly, T cells co-cultured with RANTES and IP-10 conditioned CFP10-DCs mediated killing of mycobacteria from infected macrophages. Similarly, T cells recruited by RANTES and IP-10 conditioned CFP10-DCs mediated significant killing of mycobacteria from infected macrophages. IFN-gamma treatment of CFP10-DCs restored RANTES and IP-10 levels and T cells activated by these DCs mediated significant killing of virulent M. tb inside macrophages. Adoptive transfer of either RANTES and IP-10 or IL-12 and IFN-gamma conditioned CFP10-DCs cleared an established M. tb infection in mice. The extent of clearance was similar to that obtained with drug treatment.ConclusionsThese results indicate that chemokine and cytokine secretion by DCs differentiated by M. tb antigens such as CFP-10 play major roles in regulating protective immune responses at sites of infection.

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“…A specific case report showed that the incomplete activation of the DCs in a standard immunization against leishmaniasis led to an undesirable Th2 response, resulting in lack of protection (34). In contrast, there are also cases in which a protective response is observed even in the absence of DC stimulation prior to immunization (35). Curiously, in an experimental model against TB, immunization with a DC-pulsed peptide was able to induce protection without any requirement for DC activation (36).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, other immunization studies with DCs were not able to induce protection against TB. Rubakova et al (35), in addition to showing the influence of FBS, noted a lack of protection with intravenous immunization. Furthermore, a lack of protection was also observed in conjunction with increased inflammation of the lung parenchyma when DCs pulsed with Ag85 from M. tuberculosis were administered by the intranasal route (40).…”

Section: Discussionmentioning

confidence: 99%

Antigen-presenting cells transfected with Hsp65 messenger RNA fail to treat experimental tuberculosis

Rocha

Trombone

Lorenzi

et al. 2012

Braz J Med Biol Res

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In the last several years, the use of dendritic cells has been studied as a therapeutic strategy against tumors. Dendritic cells can be pulsed with peptides or full-length protein, or they can be transfected with DNA or RNA. However, comparative studies suggest that transfecting dendritic cells with messenger RNA (mRNA) is superior to other antigen-loading techniques in generating immunocompetent dendritic cells. In the present study, we evaluated a new therapeutic strategy to fight tuberculosis using dendritic cells and macrophages transfected with Hsp65 mRNA. First, we demonstrated that antigen-presenting cells transfected with Hsp65 mRNA exhibit a higher level of expression of co-stimulatory molecules, suggesting that Hsp65 mRNA has immunostimulatory properties. We also demonstrated that spleen cells obtained from animals immunized with mock and Hsp65 mRNA-transfected dendritic cells were able to generate a mixed Th1/Th2 response with production not only of IFN-γ but also of IL-5 and IL-10. In contrast, cells recovered from mice immunized with Hsp65 mRNA-transfected macrophages were able to produce only IL-5. When mice were infected with Mycobacterium tuberculosis and treated with antigen-presenting cells transfected with Hsp65 mRNA (therapeutic immunization), we did not detect any decrease in the lung bacterial load or any preservation of the lung parenchyma, indicating the inability of transfected cells to confer curative effects against tuberculosis. In spite of the lack of therapeutic efficacy, this study reports for the first time the use of antigen-presenting cells transfected with mRNA in experimental tuberculosis.

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Specificity and efficacy of dendritic cell-based vaccination against tuberculosis with complex mycobacterial antigens in a mouse model

Cited by 12 publications

References 42 publications

Rv2299c, a novel dendritic cell-activating antigen ofMycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice

Rv2299c, a novel dendritic cell-activating antigen ofMycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice

Protective Immunity to Mycobacterium tuberculosis Infection by Chemokine and Cytokine Conditioned CFP-10 Differentiated Dendritic Cells

Antigen-presenting cells transfected with Hsp65 messenger RNA fail to treat experimental tuberculosis

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