It has been shown that senescent individuals are partially immunodeficient and possess a high risk for infections by viral and bacterial pathogens. Alterations in the first line of defense provided by the mucosal immune system has been considered to be a key element to explain the increase in susceptibility to different infectious diseases seen in the senescent population. However, our understanding of the age-associated changes in the mucosal immune system remains very limited. Nasopharyngeal-associated lymphoreticular tissues (NALT) play a central role in the induction and regulation of protective mucosal and systemic immune responses to mucosal infections. An early age-associated decline occurs in the induction and regulation of antigen (Ag)-specific mucosal and systemic immunity in the Gl tract but not in the NALT-based immunity of one yr-old mice. However, nasal immunization failed to induce mucosal immune responses in two-yr old mice despite intact NALT-induced systemic immunity. These results suggest that NALT-based immunity was less affected by aging. The hypothesis of this grant is that nasal immunization with appropriate mucosal adjuvants can actually restore Ag-specific mucosal immune responses initiated and mediated via NALT. Thus, this grant will elucidate the cellular and molecular events in the NALT immune system in aged mice given nasal vaccines. To accomplish our major goal, the first two specific aims will focus on the effects of senescence on NALT and the role of dendritic cells (DCs) in the maintenance of NALT organization as well as the induction and regulation of Ag-specific secretory IgA (S-lgA) antibody (Ab) responses. Our efforts in the last three specific aims will focus on evaluation of the efficacy of innate- and acquired-immunity mediated molecular adjuvants for the induction of protective immunity from both viral and bacterial infections in aged mice. Specifically, we will: 1) Determine the age-associated immunological changes of T and B cell function in NALT;2) Assess the role of DCs for NALT organization and initiation of Ag-specific immunity;3) Restore Ag-specific S-lgA Abs and Th1/Th2 cell responses in aged mice given plasmid of Flt3 ligand (pFL) as mucosal adjuvant;4) Evaluate the efficacy for pFL together with CpG ODN compensating for immune senescence;and 5) Determine the efficacy of DC targeting by a combination of adjuvants (pFL and CpG) against viral and bacterial pathogens in senescent mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025873-05
Application #
7904801
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fuldner, Rebecca A
Project Start
2006-09-30
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$280,028
Indirect Cost
Name
University of Alabama Birmingham
Department
Dentistry
Type
Schools of Dentistry
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Kataoka, Kosuke; Fukuyama, Yoshiko; Briles, David E et al. (2017) Dendritic cell-targeting DNA-based nasal adjuvants for protective mucosal immunity to Streptococcus pneumoniae. Microbiol Immunol 61:195-205
Sato, Shintaro; Kiyono, Hiroshi; Fujihashi, Kohtaro (2015) Mucosal Immunosenescence in the Gastrointestinal Tract: A Mini-Review. Gerontology 61:336-42
Fujihashi, Kohtaro; Sato, Shintaro; Kiyono, Hiroshi (2014) Mucosal adjuvants for vaccines to control upper respiratory infections in the elderly. Exp Gerontol 54:21-6
Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi et al. (2013) Potential roles of CCR5(+) CCR6(+) dendritic cells induced by nasal ovalbumin plus Flt3 ligand expressing adenovirus for mucosal IgA responses. PLoS One 8:e60453
Fukuyama, Yoshiko; Tokuhara, Daisuke; Sekine, Shinichi et al. (2012) Notch-ligand expression by NALT dendritic cells regulates mucosal Th1- and Th2-type responses. Biochem Biophys Res Commun 418:6-11
Hong, Seol Hee; Byun, Young-Ho; Nguyen, Chung Truong et al. (2012) Intranasal administration of a flagellin-adjuvanted inactivated influenza vaccine enhances mucosal immune responses to protect mice against lethal infection. Vaccine 30:466-74
Fujkuyama, Yoshiko; Tokuhara, Daisuke; Kataoka, Kosuke et al. (2012) Novel vaccine development strategies for inducing mucosal immunity. Expert Rev Vaccines 11:367-79
Asanuma, Hideki; Zamri, Normaiza Binti; Sekine, Shinichi et al. (2012) A novel combined adjuvant for nasal delivery elicits mucosal immunity to influenza in aging. Vaccine 30:803-12
Kataoka, Kosuke; Fujihashi, Keiko; Terao, Yutaka et al. (2011) Oral-nasopharyngeal dendritic cells mediate T cell-independent IgA class switching on B-1 B cells. PLoS One 6:e25396
Kataoka, Kosuke; Fujihashi, Kohtaro; Oma, Keita et al. (2011) The nasal dendritic cell-targeting Flt3 ligand as a safe adjuvant elicits effective protection against fatal pneumococcal pneumonia. Infect Immun 79:2819-28

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