A Combination of Flt3 Ligand cDNA and CpG Oligodeoxynucleotide as Nasal Adjuvant Elicits Protective Secretory-IgA Immunity to Streptococcus pneumoniae in Aged Mice

Abstract

Our previous study showed that a combination of a plasmid-expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotides (CpG ODN) as a combined nasal adjuvant elicited mucosal immune responses in aged (2-y-old) mice. In this study, we investigated whether a combination of pFL and CpG ODN as a nasal adjuvant for a pneumococcal surface protein A (PspA) would enhance PspA-specific secretory-IgA Ab responses, which could provide protective mucosal immunity against Streptococcus pneumoniae infection in aged mice. Nasal immunization with PspA plus a combination of pFL and CpG ODN elicited elevated levels of PspA-specific secretory-IgA Ab responses in external secretions and plasma in both young adult and aged mice. Significant levels of PspA-specific CD4+ T cell proliferative and PspA-induced Th1- and Th2- type cytokine responses were noted in nasopharyngeal-associated lymphoreticular tissue, cervical lymph nodes, and spleen of aged mice, which were equivalent to those in young adult mice. Additionally, increased numbers of mature-type CD8, CD11b-expressing dendritic cells were detected in mucosal inductive and effector lymphoid tissues of aged mice. Importantly, aged mice given PspA plus a combination of pFL and CpG ODN showed protective immunity against nasal S. pneumoniae colonization. These results demonstrate that nasal delivery of a combined DNA adjuvant offers an attractive possibility for protection against S. pneumoniae in the elderly.

Pneumococcal Capsular Polysaccharide Immunity in the Elderly

“…This same adjuvant restored the antibody response of aged mice to conjugated serotype 14 CPS administered systemically (110). For nasally administered pneumococcal surface protein A (PspA), a dual-adjuvant strategy of CpG-ODN and a plasmid expressing Flt3 ligand was required to induce similar antibody levels (serum and mucosal IgG and IgA) in young and old mice (111). This strategy also enhanced PspA-specific CD4 ϩ T cell responses in old mice and protected these mice against nasopharyngeal colonization.…”

Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination

“…Stimulation of human B cells with FL in vitro potentiate anti-IgM-induced proliferation and survival (29). Also, FL has potent adjuvant effects in vivo, enhancing protective IgA immunity in streptococcal pneumonia (33). Taken together, these results suggest that Flt3 may participate in processes associated with B-cell activation.…”

Cationic pullulan nanogel as a safe and effective nasal vaccine delivery system for respiratory infectious diseases

“…27 In addition, nasal immunization of PspA with mucosal adjuvants, such as a plasmid-expressed Flt3 ligand and CpG oligodeoxynucleotides, yielded PspA-specific SIgA in aged or pregnant mice. 28 After nasal vaccination, bacterial colonization was inhibited even in 2-year-old (that is, aged) mice and in pups born to vaccinated dams. 28 , 29 These results support PspA as a promising antigen candidate for an S. pneumoniae vaccine that is likely to be effective not only in adults but also in children and the elderly.…”

“…28 After nasal vaccination, bacterial colonization was inhibited even in 2-year-old (that is, aged) mice and in pups born to vaccinated dams. 28 , 29 These results support PspA as a promising antigen candidate for an S. pneumoniae vaccine that is likely to be effective not only in adults but also in children and the elderly. 30 , 31 …”