SummaryWe explore cellular and molecular mechanisms of nasal adjuvant of a combination of a plasmid encoding the Flt3 ligand cDNA (pFL) and CpG oligodeoxynucleotides (CpG ODN). The double DNA adjuvant given with OVA maintained prolonged OVA-specific secretory IgA (S-IgA) Ab responses in external secretions for more than twenty-five weeks after the final immunization. Further, both Th1-and Th2-type cytokine responses were induced by this combined adjuvant regimen. The frequencies of plasmacytoid DCs (pDCs) and CD8 + DCs were significantly increased in nasopharyngeal-associated lymphoreticular tissue (NALT) of mice given the combined adjuvant. Importantly, when we examined adjuvanticity of pFL plus CpG ODN in 2-year-old mice, significant levels of mucosal IgA Ab responses were also induced. These results demonstrate that nasal delivery of a combined DNA adjuvant offers an attractive possibility for the development of an effective mucosal vaccine for the elderly.

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Since a combination of flt3 ligand plasmid (pFL) and CpG-oligodeoxynucleotides (ODN)3 as a dendritic cell (DC)-targeting double mucosal adjuvant elicited ovalbumin-specific secretory IgA (S-IgA) antibody (Ab) responses, we examined whether this double adjuvant could induce influenza-specific protective immunity in aged mice. A double adjuvant plus A/Puerto Rico/8/34 (PR8)-hemagglutinin (HA) induced increased numbers of CD11b+ CD11c+DCs and both CD4+ Th1- and Th2-type responses in the nasopharyngeal-associated lymphoreticular tissue, nasal passages and cervical lymph nodes. Further, increased levels of PR8-HA-specific S-IgA Ab responses were detected in the upper respiratory tact (URT) of aged and young adult mice given nasal PR8-HA with this double adjuvant. Thus, when mice were challenged with PR8 virus via the nasal route, both aged and young adult mice given nasal vaccine exhibited complete protection. Further, IgA-deficient mice nasally immunized with a double adjuvant influenza vaccine failed to provide protection against PR8 challenge. These results indicate that a nasal double adjuvant successfully induces PR8-HA-specific IgA Ab responses in both young adult and aged mice, which are essential for the prevention of influenza infection in the murine URT.

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Background-One of the pathological hallmarks of Alzheimer disease (AD) is deposits of amyloid β-peptide (Aβ) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Aβ reduces Aβ deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Aβ were halted due to brain inflammation that was presumably induced by a T cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed.Methods-We have nasally immunized young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Aβ1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Aβ1-6) 11 , in order to evaluate the efficacy of the vector in preventing Aβ deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Aβ1-6) 11 .Results-Nasal immunization of an AD mouse model with AdPEDI-(Aβ1-6) 11 elicited a predominant IgG1 response and reduced Aβ load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Aβ1-6) 11 , marked IL-10 responses were found in splenic CD4 + T cells from C57BL/6 mice that had been immunized with AdPEDI-(Aβ1-6) 11 .Conclusions-These results suggest that the induction of Th2-biased responses with AdPEDI-(Aβ1-6) 11 in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.