Intranasal Immunization Promotes Th17 Immune Responses

Zygmunt, Beata M.; Rharbaoui, Faı̈za; Groebe, Lothar; Guzmán, Carlos A.

doi:10.4049/jimmunol.0901144

Cited by 75 publications

(63 citation statements)

References 23 publications

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“…Thus, mice given S. pneumoniae mixed with NWs from vaccinated IgA 2/2 mice also showed elevated CFUs in the nasal cavity; however, mice that received the mixture of S. pneumoniae and S-IgA anti-PspA Abs from NWs of vaccinated IgA +/+ mice had no detectable CFUs. A recent report showed the importance of IL-17 synthesis for protection against pneumococcal infection (34)(35)(36). Although IgA 2/2 mice given nasal PspA plus pFL exhibited increased levels of IL-17-producing CD4 + T cells as did IgA +/+ mice, this mutant mouse strain failed to prevent colonization of S. pneumoniae.…”

Section: Discussionmentioning

confidence: 99%

Secretory-IgA Antibodies Play an Important Role in the Immunity to Streptococcus pneumoniae

Fukuyama

King

Kataoka

et al. 2010

The Journal of Immunology

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This study was designed to investigate whether secretory-IgA (S-IgA) Abs induced by a pneumococcal surface protein A (PspA)-based nasal vaccine are necessary for prevention of streptococcal colonization. Mice nasally immunized with PspA plus a plasmid expressing Flt3 ligand (pFL) cDNA as a mucosal adjuvant showed significantly higher levels of PspA-specific S-IgA and IgG Ab responses in both plasma and nasal washes when compared with naive mice. Although IgA−/− mice given nasal PspA plus pFL had significantly high levels of PspA-specific IgG Abs, high numbers of CFUs were detected in nasal washes and nasal passages. In contrast, vaccinated wild-type mice showed essentially no bacteria in the nasal cavity. Further, a nasal vaccine consisting of PspA plus pFL effectively reduced pre-existing Streptococcus pneumoniae in the nasal cavity. These results show that PspA-based vaccine-induced specific S-IgA Abs play a necessary role in the regulation of S. pneumoniae colonization in the nasal cavity.

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Section: Discussionmentioning

confidence: 99%

Secretory-IgA Antibodies Play an Important Role in the Immunity to Streptococcus pneumoniae

Fukuyama

King

Kataoka

et al. 2010

The Journal of Immunology

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“…Interestingly, neutrophils predominantly infiltrated the airways of RORgt-overexpressing mice, with enhanced lung expression of IL-17A and IL-22 after exposure to the same Ag. IL-17 is increased in the airways of persistent asthma sufferers (4,21) and in asthma animal models (22)(23)(24), and the increased levels of IL-17 in the airways were accompanied by neutrophilic infiltration. Although IL-17 can be produced by numerous cell types, we propose that Th17 cells are the main source of IL-17A in our RORgt-overexpressing asthmatic mouse model.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors GATA-3 and RORγt Are Important for Determining the Phenotype of Allergic Airway Inflammation in a Murine Model of Asthma

Ano

Morishima

Ishii

et al. 2013

The Journal of Immunology

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In refractory asthma, neutrophils, rather than eosinophils, often predominate in the airways. Neutrophilic airway inflammation appears to be resistant to steroids and may be related to the Th17, rather than the Th2, cytokine milieu. However, the role of GATA-3 and RORγt, transcription factors for Th2 and Th17 cell differentiation, respectively, in the pathogenesis of steroid-insensitive asthma remains unclear. To examine the effect of GATA-3– and RORγt-overexpression backgrounds on airway inflammation and steroid sensitivity, we generated two strains of transgenic mice overexpressing GATA-3 or RORγt. Mice were sensitized and challenged with OVA. Some OVA-sensitized/challenged mice were treated with dexamethasone, anti–IL-17 Ab, CXCR2 antagonist, or anti–IL-6R Ab to demonstrate their therapeutic effects on airway inflammation. Although Ag-specific airway inflammation and hyperresponsiveness were induced in each mouse, the phenotype of inflammation showed a distinct difference that was dependent upon the genotype. GATA-3–overexpressing mice exhibited steroid-sensitive eosinophilic inflammation with goblet cell hyperplasia and mucus hyperproduction under Th2-biased conditions, and RORγt-overexpressing mice developed steroid-insensitive neutrophilic inflammation under Th17-biased conditions. The levels of keratinocyte-derived chemokine, MIP-2, IL-6, and other neutrophil chemotaxis-related mediators were significantly elevated in OVA-exposed RORγt-overexpressing mice compared with wild-type mice. Interestingly, airway hyperresponsiveness accompanied by neutrophilic airway inflammation in RORγt-overexpressing mice was effectively suppressed by anti–IL-17 Ab, CXCR2 antagonist, or anti–IL-6R Ab administration. In conclusion, our results suggest that the expression levels of GATA-3 and RORγt may be important for determining the phenotype of asthmatic airway inflammation. Furthermore, blockade of the Th17-signaling pathway may be a treatment option for steroid-insensitive asthma.

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“…We did not assess the vaccine potential of FpvA due to the recently described high genetic variation of the fpvA gene, resulting in extensive sequence polymorphism of this protein when expressed by different P. aeruginosa strains (32,33). We used an intranasal immunization route and combined the proteins with the Th17 adjuvant curdlan (a b-(1, 3)-linked glucose polymer that composes the b-D-glucan of the fungal cell wall), which has been shown to promote Th17 responses (17,18). Importantly, despite mucosal administration of a Th17 adjuvant and a protein with Th epitopes (PopB) during vaccination, there was no evidence of lung inflammation on histology ( Figure E2A), and BALF neutrophil numbers were not elevated when assessed 3 weeks after the third intranasal immunization ( Figure E2B).…”

Section: Protective Efficacy Of Popb Vaccinationmentioning

confidence: 99%

“…Indeed, it is not the nature of the protein antigen that determines the lineage decisions of immature Th cells but rather the context of the initial interaction of the naive T cell with antigenpresenting cells (16). Thus, we tested whether a known Th17 adjuvant, curdlan (17,18), would improve the Th17 responses after immunization with the purified proteins. We found that immunization of mice with PopB-curdlan elicited strong Th17 responses against P. aeruginosa and conferred IL-17-dependent protection from lethal P. aeruginosa lung infection in the absence of opsonophagocytic antibody.…”

mentioning

confidence: 99%

Th17-stimulating Protein Vaccines Confer Protection against Pseudomonas aeruginosa Pneumonia

Jin

Duan

et al. 2012

Am J Respir Crit Care Med

112

155

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Rationale: New vaccine approaches are needed for Pseudomonas aeruginosa, which continues to be a major cause of serious pulmonary infections. Although Th17 cells can protect against gram-negative pathogens at mucosal surfaces, including the lung, the bacterial proteins recognized by Th17 cells are largely unknown and could be potential new vaccine candidates. Objectives: We describe a strategy to identify Th17-stimulating protein antigens of Pseudomonas aeruginosa to assess their efficacy as vaccines against pneumonia.Methods: Using a library of in vitro transcribed and translated P. aeruginosa proteins, we screened for Th17-stimulating antigens by coculturing the library proteins with splenocytes from mice immunized with a live-attenuated P. aeruginosa vaccine that is protective via Th17-based immunity. We measured antibody and Th17 responses after intranasal immunization of mice with the purified proteins mixed with the Th17 adjuvant curdlan, and we tested the protective efficacy of vaccination in a murine model of acute pneumonia. Measurements and Main Results: The proteins PopB, FpvA, FptA, OprL, and PilQ elicited strong IL-17 secretion in the screen, and purified versions of PopB, FpvA, and OprL stimulated high IL-17 production from immune splenocytes. Immunization with PopB, which is a highly conserved component of the type III secretion system and a known virulence factor, elicited Th17 responses and also enhanced clearance of P. aeruginosa from the lung and spleen after challenge. PopB-immunized mice were protected from lethal pneumonia in an antibody-independent, IL-17-dependent manner. Conclusions: Screening for Th17-stimulating protein antigens identified PopB as a novel and promising vaccine candidate for P. aeruginosa.Keywords: vaccine; pneumonia; Th17; IL-17; Pseudomonas aeruginosa Pseudomonas aeruginosa is a major cause of serious, often antibiotic-resistant, lung infections in humans, particularly in patients receiving mechanical ventilation and those with cystic fibrosis (1, 2). Most P. aeruginosa vaccines developed to date, including those based on the LPS O antigen (3), the outer membrane proteins F and I (4, 5), or the type III secretion system component PcrV (6), have relied on conventional protective mechanisms-namely, antibody-mediated opsonophagocytic killing and/or antibody-mediated toxin inhibition. Although LPS O antigen-based vaccines can mediate high levels of immunity to P. aeruginosa, the protection is limited to strains having the same LPS serogroup (3). The failure of the Federal Hyperimmune Immunoglobulin Trial (7), which found no benefit in critically ill adults passively immunized with P. aeruginosa LPS O antigenspecific IgG, perhaps best illustrates that antibody-mediated protective mechanisms are not sufficient.Th17 cells have recently been shown to mediate antibodyindependent host defense against Klebsiella pneumoniae (8), although the bacterial proteins recognized by the Th17 cells in those studies were not fully characterized. In our own evaluations of live-attenuated P. ...

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Intranasal Immunization Promotes Th17 Immune Responses

Cited by 75 publications

References 23 publications

Secretory-IgA Antibodies Play an Important Role in the Immunity to Streptococcus pneumoniae

Secretory-IgA Antibodies Play an Important Role in the Immunity to Streptococcus pneumoniae

Transcription Factors GATA-3 and RORγt Are Important for Determining the Phenotype of Allergic Airway Inflammation in a Murine Model of Asthma

Th17-stimulating Protein Vaccines Confer Protection against Pseudomonas aeruginosa Pneumonia

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