Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jun;61(6):195-205.
doi: 10.1111/1348-0421.12487.

Dendritic cell-targeting DNA-based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae

Kosuke Kataoka  1 , Yoshiko Fukuyama  2 , David E Briles  2 , Tatsuro Miyake  1 , Kohtaro Fujihashi  2
Affiliations
Review

Dendritic cell-targeting DNA-based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae

Kosuke Kataoka et al. Microbiol Immunol. 2017 Jun.

Abstract

To develop safe vaccines for inducing mucosal immunity to major pulmonary bacterial infections, appropriate vaccine antigens (Ags), delivery systems and nontoxic molecular adjuvants must be considered. Such vaccine constructs can induce Ag-specific immune responses that protect against mucosal infections. In particular, it has been shown that simply mixing the adjuvant with the bacterial Ag is a relatively easy means of constructing adjuvant-based mucosal vaccine preparations; the resulting vaccines can elicit protective immunity. DNA-based nasal adjuvants targeting mucosal DCs have been studied in order to induce Ag-specific mucosal and systemic immune responses that provide essential protection against microbial pathogens that invade mucosal surfaces. In this review, initially a plasmid encoding the cDNA of Flt3 ligand (pFL), a molecule that is a growth factor for DCs, as an effective adjuvant for mucosal immunity to pneumococcal infections, is introduced. Next, the potential of adding unmethylated CpG oligodeoxynucleotide and pFL together with a pneumococcal Ag to induce protection from pneumococcal infections is discussed. Pneumococcal surface protein A has been used as vaccine for restoring mucosal immunity in older persons. Further, our nasal pFL adjuvant system with phosphorylcholine-keyhole limpet hemocyanin (PC-KLH) has also been used in pneumococcal vaccine development to induce complete protection from nasal carriage by Streptococcus pneumoniae. Finally, the possibility that anti-PC antibodies induced by nasal delivery of pFL plus PC-KLH may play a protective role in prevention of atherogenesis and thus block subsequent development of cardiovascular disease is discussed.

Keywords: DNA-based adjuvants; Streptococcus pneumoniae; dendritic cells; nasal vaccination.

PubMed Disclaimer

Conflict of interest statement

DISCLOSURE

The authors declare that they have no conflicts of interest for this article.

Figures

Fig. 1
Fig. 1. Induction of Ag-specific mucosal SIgA Ab responses via the Common Mucosal Immune System
Ag derived from foreign compounds is presented by APCs beneath mucosal surfaces to naïve lymphocytes within inductive sites of organized mucosal lymphoid tissues, e.g., NALT and GALT. Activated lymphocytes leave these tissues via draining lymph nodes and reenter mucosal effector tissue sites throughout the body from the circulation, and subsequently establish mucosal immune responses.
Fig. 2
Fig. 2. Nasal dendritic cell-targeting adjuvant systems using pFL and/or CpG ODN for induction of protective mucosal immunity
Nasal pFL as mucosal adjuvant preferentially expands the CD8+ DCs and subsequently elicits Th2-type cytokine-mediated Ag-specific Ab responses. In contrast, CpG ODN activates B220+ pDCs for the induction of Th1-type, CMI, CTLs and Ag-specific SIgA Ab responses. Thus, a combined nasal adjuvant consisting of both pFL and CpG ODN stimulates both CD8+ DCs and pDCs and successfully induces Th1- and Th2- directed Ag-specific SIgA Ab responses.
Fig. 3
Fig. 3. Comparison of protective effects against S. pneumoniae infection with a nasal pFL vaccine
One weeks after the last immunization with PspA plus pFL (closed circle) or pORF (open circle), mice were challenged with 1.8 X 107 CFUs of live S. pneumoniae in suspension. Forty eight hr after bacterial challenge, NWs were harvested aseptically by flushing with 1 ml of sterile PBS and cultured on agar medium. The lungs were removed aseptically and homogenized in 9 ml of sterile saline per gram of lung tissue for culture. After overnight incubation at 37° C in 5 % CO2, the numbers of individual bacterial colonies were counted. The concentration of S. pneumoniae was expressed as CFUs per ml. The closed circles represent CFUs from mice given nasal PspA plus pFL, while the open circles indicate CFUs from mice nasally immunized with PspA plus pORF. Each line represents the median Log10 CFU per mouse. A 95 percent confidence interval (*) was used to determine statistical significance between the test group and the control group given PspA and pORF.
Fig. 4
Fig. 4. Comparison of PspA-specific IgA Ab responses in external secretions and plasma of aged mice
Aged mice were nasally immunized with 5 μg of PspA and 50 μg of pFL or 10 μg of CpG ODN (open column), or 5 μg of PspA and 50 μg of pFL plus 10 μg of CpG ODN (closed column) three times at weekly intervals. Seven days after the final immunization, levels of anti-PspA SIgA Abs in NWs, saliva and IgA in plasma were determined by PspA-specific ELISA. ND: optical density values were not detected. The values shown are the mean ± SEM. A 95 percent confidence interval is indicated (*).
Fig. 5
Fig. 5. Nasal pFL as mucosal adjuvant enhances anti-PC Ab responses in both mucosal and systemic immune compartments
C57BL/6 mice were nasally immunized with PC-KLH plus pFL (closed column) or control pORF (open column) as mucosal adjuvant weekly for three consecutive weeks. Seven days after the final immunization, the levels of anti-PC IgA, IgM and IgG Abs in NWs, BALF and plasma were determined by PC-specific ELISA. The values are the mean ± SEM. A 95 percent confidence interval is indicated (*). BALF, denotes bronchoalveolar lavage fluids.
Fig. 6
Fig. 6. The inhibition of S. pneumoniae colonization in the upper respiratory tract by a nasal dendritic cell-targeting adjuvant system for prevention of pneumococcal infection
C57BL/6 mice were nasally immunized with PC-KLH plus pFL (closed column) or control pORF (open column) as mucosal adjuvant weekly for three consecutive weeks. Aliquots of 2.0 × 107 CFUs of live S. pneumoniae in suspension were nasally administered seven days after the final immunization. Twelve hr later, mice were sacrificed and BALF and NWs were obtained. The samples were diluted in sterile PBS and spread on blood agar plates. After overnight incubation at 37° C in 5 % CO2, the numbers of individual bacterial colonies were counted. The concentration of S. pneumoniae was expressed as CFUs per ml. The closed circles represent CFUs from mice given nasal PC-KLH plus pFL, while the open circles indicate CFUs from mice nasally immunized with PC-KLH plus pORF. Each line represents the median Log10 CFU per mouse. A 95 percent confidence interval is indicated (*) and was used to determine statistical significance between the test group and the control group given PC-KLH and pORF. BALF, denotes bronchoalveolar lavage fluids.
Fig. 7
Fig. 7. A novel type of pneumococcal vaccine with dendritic cell-targeting DNA-based nasal adjuvant
Nasal delivery of PC-KLH plus pFL resulted in inhibition of S. pneumoniae colonization in the upper and lower respiratory tracts, concurrent with the expansion of mucosal DCs and enhancement of anti-PC Ab production. In addition, this nasal vaccination increased the numbers of B-1 B cells producing the T15 idiotype in mucosal effector tissues. It should now be possible to consider use of a nasal PC-KLH plus pFL vaccine which could also exhibit anti-atherosclerotic effects.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. O’Brien KL, Wolfson LJ, Watt JP, Henkle E, Deloria-Knoll M, McCall N, Lee E, Levine OS, Hajjeh R, Mulholland K, Cherian T. Hib and pneumococcal global burden of disease study team. Burden of diseases caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374:893–902. - PubMed
    1. Croney CM, Coats MT, Nahm MH, Briles DE, Crain MJ. PspA family distribution, unlike capsular serotype, remains unaltered following introduction of the heptavalent pneumococcal conjugate vaccine. Clin Vaccine Immunol. 2012;19:891–896. - PMC - PubMed
    1. Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, Reingold A, Thomas A, Schaffner W, Craig AS, Smith PJ, Beall BW, Whitney CG, Moore MR. Active Bacterial Core Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32–41. - PubMed
    1. Fukuyama Y, King JD, Kataoka K, Kobayashi R, Gilbert RS, Oishi K, Hollingshead SK, Briles DE, Fujihashi K. Secretory-IgA antibodies play an important role in the immunity to Streptococcus pneumoniae. J Immunol. 2010;185:1755–1762. - PubMed
    1. Fujihashi K, Boyaka PN, McGhee JR. Host defenses at mucosal surfaces. In: Rich RT, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM, editors. Clinical Immunology. Philadelphia, PA: Elsevier; 2013. pp. 239–251.

MeSH terms