Dendritic Cell‐Based Vaccine against <i>Coccidioides</i> Infection

Awasthi, Shanjana

doi:10.1196/annals.1406.013

Cited by 17 publications

(11 citation statements)

References 35 publications

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“…Dendritic cells are potent antigen-presenting cells (APCs) and play a key role in the activation of naïve T lymphocytes in response to coccidioidal infection (2,10). Stimulation of CD4 ϩ T cells in a vaccine-induced host response to Coccidioides is pivotal for protection against coccidioidomycosis (6).…”

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confidence: 99%

Evaluation of Two Homologous Proline-Rich Proteins of Coccidioides posadasii as Candidate Vaccines against Coccidioidomycosis

2007

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Evaluation of the protective efficacy of recombinant T-cell-reactive proteins of Coccidioides posadasii in a murine model of coccidioidomycosis has led to the discovery of potential vaccines against this respiratory disease. A recombinant proline-rich antigen (rAg2/Pra) has been reported to be a leading vaccine candidate. However, contradictory results exist on the protection afforded by this antigen. Subcutaneous vaccination of either C57BL/6 or BALB/c mice with rAg2/Pra plus adjuvant followed by intraperitoneal challenge with C. posadasii resulted in a significant reduction of the fungal burden at 12 to 14 days postchallenge compared to that in nonvaccinated animals. Use of the same vaccination protocol followed by intranasal (i.n.) challenge of C57BL/6 mice with an equal number of organisms culminated in chronic pulmonary infection or death over a 90-day period. Early studies of Ag2/Pra suggested that it is a component of an immunogenic complex. We reveal in this study that C. posadasii produces a homolog of the reported proline-rich antigen, designated Prp2, which shows 69% protein sequence identity and 86% similarity to Ag2/Pra. Protection against i.n. challenge of C57BL/6 mice was evaluated by vaccination with the single bacterially expressed homolog, rAg2/Pra, or rPrp2 in combination with rAg2/Pra, each in the presence of the same adjuvant. The combined vaccine provided significantly better protection than either of the single recombinant protein vaccines. Results of enzyme-linked immunospot assays of the immunized mice revealed that the two proline-rich homologs contain unique T-cell epitopes. In combination, the recombinant proteins stimulate a more heterogeneous and protective T-cell repertoire than the monovalent vaccines.

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confidence: 99%

Evaluation of Two Homologous Proline-Rich Proteins of Coccidioides posadasii as Candidate Vaccines against Coccidioidomycosis

2007

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“…In this regard, DCs infected in vitro with BCG activated T cell responses in the lung, but this level of immune activation was protective only within the short term (17). Although plasmid DNA-transduced DCs activated IFN-␥ responses following mucosal DC immunization, neither the cellular source of the IFN-␥ nor the kinetics of immune activation was examined (8,19). To date, there has been a lack of comprehensive understanding of the immune activation and mechanisms at mucosal surfaces following DC immunization.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, i.n. delivery of the DCs genetically modified with plasmid DNA encoding a microbial Ag, only minimally enhanced T cell responses and protection from Coccidioides challenge (8,19). Such limited success in mucosal DC immunization is believed to be attributable at least in part to our lack of knowledge in DC trafficking, immunogenic differences by mucosal and parenteral routes of delivery, and the mechanisms involved in DC mucosal immunization.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Mucosally Delivered Dendritic Cells Activate T Cells Independently of IL-12 and Endogenous APCs

McCormick

Santosuosso

Small

et al. 2008

The Journal of Immunology

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In vitro manipulated dendritic cells (DC) have increasingly been used as a promising vaccine formulation against cancer and infectious disease. However, improved understanding of the immune mechanisms is needed for the development of safe and efficacious mucosal DC immunization. We have developed a murine model of respiratory mucosal immunization by using a genetically manipulated DC vaccine. Within 24 h of intranasal delivery, the majority of vaccine DCs migrated to the lung mucosa and draining lymph nodes and elicited a significant level of T cells capable of IFN-γ secretion and CTL in the airway lumen as well as substantial T cell responses in the spleen. And such T cell responses were associated with enhanced protection against respiratory mucosal intracellular bacterial challenge. In comparison, parenteral i.m. DC immunization did not elicit marked airway luminal T cell responses and immune protection regardless of strong systemic T cell activation. Although repeated mucosal DC delivery boosted Ag-specific T cells in the airway lumen, added benefits to CD8 T cell activation and immune protection were not observed. By using MHC-deficient vaccine DCs, we further demonstrated that mucosal DC immunization-mediated CD8 and CD4 T cell activation does not require endogenous DCs. By using IL-12-deficient vaccine DCs, we also observed that IL-12−/− DCs failed to migrate to the lymph nodes but remained capable of T cell activation. Our observations indicate that mucosal delivery of vaccine DCs represents an effective approach to enhance mucosal T cell immunity, which may operate independent of vaccine IL-12 and endogenous DCs.

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“…The ability of a given DC subset to respond with distinct intracellular signaling pathways to different PRR/fungal molecule combinations confers DCs with the unique ability to orchestrate adaptive immune responses to fungi and to improve vaccine efficacy [10,[57][58][59][60][61][62][63]. There is reason to expect that combinations of adjuvants that target multiple PRRs and various other intracellular alarm systems on the right DC subsets will prove the most effective for achieving effective antibody and T cell memory [64].…”

Section: Reviewmentioning

confidence: 99%