The Nasal Dendritic Cell-Targeting Flt3 Ligand as a Safe Adjuvant Elicits Effective Protection against Fatal Pneumococcal Pneumonia

Kataoka, Kosuke; Fujihashi, Kohtaro; Oma, Keita; Fukuyama, Yoshiko; Hollingshead, Susan K.; Sekine, Shinichi; Kawabata, Shigetada; Itô, Haruo; Briles, David E.; Oishi, Kazunori

doi:10.1128/iai.01360-10

Cited by 32 publications

(31 citation statements)

References 42 publications

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“…9A). Based on analysis of NALT, optimization of adjuvant formulations to improve mucoadhesion and to specifically target NALT antigen-presenting cells (66)(67)(68) would be expected to improve the protective efficacy of i.n. delivered flagellin-CS vaccines.…”

Section: Discussionmentioning

confidence: 99%

Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

et al. 2013

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bImmunization with Plasmodium sporozoites can elicit high levels of sterile immunity, and neutralizing antibodies from protected hosts are known to target the repeat region of the circumsporozoite (CS) protein on the parasite surface. CS-based subunit vaccines have been hampered by suboptimal immunogenicity and the requirement for strong adjuvants to elicit effective humoral immunity. Pathogen-associated molecular patterns (PAMPs) that signal through Toll-like receptors (TLRs) can function as potent adjuvants for innate and adaptive immunity. We examined the immunogenicity of recombinant proteins containing a TLR5 agonist, flagellin, and either full-length or selected epitopes of the Plasmodium falciparum CS protein. Mice immunized with either of the flagellin-modified CS constructs, administered intranasally (i.n.) or subcutaneously (s.c.), developed similar levels of malaria-specific IgG1 antibody and interleukin-5 (IL-5)-producing T cells. Importantly, immunization via the i.n. but not the s.c. route elicited sporozoite neutralizing antibodies capable of inhibiting >90% of sporozoite invasion in vitro and in vivo, as measured using a transgenic rodent parasite expressing P. falciparum CS repeats. These findings demonstrate that functional sporozoite neutralizing antibody can be elicited by i.n. immunization with a flagellin-modified P. falciparum CS protein and raise the potential of a scalable, safe, needle-free vaccine for the 40% of the world's population at risk of malaria.

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Section: Discussionmentioning

confidence: 99%

Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

et al. 2013

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“…1A). Mononuclear cells from the mediastinal lymph nodes (MeLNs) and spleen were isolated under aseptic conditions by the mechanical dissociation method as described previously (14,17). Nasal passages (NPs) were isolated using a modification of the dissociation method described previously (14,15,17).…”

Section: Methodsmentioning

confidence: 99%

“…Mononuclear cells from the mediastinal lymph nodes (MeLNs) and spleen were isolated under aseptic conditions by the mechanical dissociation method as described previously (14,17). Nasal passages (NPs) were isolated using a modification of the dissociation method described previously (14,15,17). Mononuclear cells were isolated from the lungs by a combination of an enzymatic dissociation procedure using collagenase type IV (0.5 mg/ml; Sigma-Aldrich, St. Louis, MO) followed by discontinuous Percoll (Amersham Biosciences, Piscataway, NJ) gradient centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

Takahashi

Kataoka

Indalao

et al. 2012

J Virol

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We previously reported that the macrolide antibiotic clarithromycin (CAM) enhanced the mucosal immune response in pediatric influenza, particularly in children treated with the antiviral neuraminidase inhibitor oseltamivir (OSV) with low production of mucosal antiviral secretory IgA (S-IgA). The aims of the present study were to confirm the effects of CAM on S-IgA immune responses, by using influenza A virus (IAV) H1N1-infected mice treated with or without OSV, and to determine the molecular mechanisms responsible for the induction of mucosal IgA class switching recombination in IAV-infected CAM-treated mice. The anti-IAV S-IgA responses and expression levels of IgA class switching recombination-associated molecules were examined in bronchus-lymphoid tissues and spleens of infected mice. We also assessed neutralization activities of S-IgA against IAV. Data show that CAM enhanced anti-IAV S-IgA induction in the airway of infected mice and restored the attenuated antiviral S-IgA levels in OSV-treated mice to the levels in the vehicle-treated mice. The expression levels of B-cell-activating factor of the tumor necrosis factor family (BAFF) molecule on mucosal dendritic cells as well as those of activation-induced cytidine deaminase and Iμ-Cα transcripts on B cells were enhanced by CAM, compared with the levels without CAM treatment, but CAM had no effect on the expression of the BAFF receptor on B cells. Enhancement by CAM of neutralization activities of airway S-IgA against IAV in vitro and reinfected mice was observed. This study identifies that CAM enhances S-IgA production and neutralizing activities through the induction of IgA class switching recombination and upregulation of BAFF molecules in mucosal dendritic cells in IAV-infected mice.

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“…In the past few years, Flt3L has been used in immunization strategies aimed at preventing airborne bacterial infections. For example, Flt3L administration, when used in murine vaccination studies, enhances mucosal immunity against Streptococcus pneumoniae and improves protective immunity against Mycobacterium tuberculosis (24,48). Moreover, in preclinical cancer models, Flt3L administration expands DC populations and supports the generation of a specific antitumor response in mice, resulting in tumor regression (2,34).…”

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confidence: 99%

FMS-Like Tyrosine Kinase 3 Ligand Treatment of Mice Aggravates Acute Lung Injury in Response to Streptococcus pneumoniae: Role of Pneumolysin

et al. 2012

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The Nasal Dendritic Cell-Targeting Flt3 Ligand as a Safe Adjuvant Elicits Effective Protection against Fatal Pneumococcal Pneumonia

Cited by 32 publications

References 42 publications

Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

Oral Clarithromycin Enhances Airway Immunoglobulin A (IgA) Immunity through Induction of IgA Class Switching Recombination and B-Cell-Activating Factor of the Tumor Necrosis Factor Family Molecule on Mucosal Dendritic Cells in Mice Infected with Influenza A Virus

FMS-Like Tyrosine Kinase 3 Ligand Treatment of Mice Aggravates Acute Lung Injury in Response to Streptococcus pneumoniae: Role of Pneumolysin

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