The earlier FIRST award focused on elucidation of the underlying molecular and cellular mechanisms for the induction and regulation of antigen-specific secretory IgA (S-IgA) antibody (Ab) responses at mucosal surfaces with emphasis on the salivary glands. The earlier studies have produced important results indicating that a mucosal intranet consisting of alpha,beta-T cells, gammadelta T cells and epithelial cells played major roles in the induction and regulation of antigen-specific IgA Ab responses. Thus, nasal immunization with the weakly immunogenic protein ovalbumin (OVA) and the nonenterotoxic mutant cholera toxin (CT) as mucosal adjuvant induced Th2-type cytokine-mediated salivary S-IgA Ab responses. Interestingly, depletion of gammadelat T cells resulted in impaired mucosal IgA responses including those responses in saliva. Further, these findings showed that epithelial cells produced an important cytokine, i.e., interleukin (IL)-7 which is central to the development and differentiation of alphabeta T cells. These results clearly indicate that lymphocyte- epithelial cell interactions, representing innate and acquired immunity, are part of the mechanisms involved in the induction of antigen-specific IgA Ab responses. These findings suggest that the innate immune system may be a key element in bridging innate with acquired mucosal immunity as manifested by antigen-specific IgA responses. Recent studies have indeed shown that nasal application of defensins, or chemokines such as lymphotactin or RANTES with OVA induced OVA-specific mucosal IgA Ab responses, including those associated with the salivary glands. Further, most recent findings through this grant effort showed that mRNA for these chemokines were expressed by intestinal and salivary gammadelta T cells as well as by epithelial cells. Thus, the overall hypothesis in this grant renewal application will be that the innate mucosal immune system plays an especially important role in acquired immunity for the induction and regulation of salivary gland IgA Ab responses. In order to understand the precise cellular and molecular mechanisms involved in innate immunity for mucosal IgA responses, the following Specific Aims are proposed. Specifically, there are plans to: 1) Characterize innate immunity in salivary glands of mice immunized with a hapten-LPS derivative of T-independent (TI) antigen ; 2)Examine the roles for innate immunity-associated mucosal modulators for the induction of TI-antigen-specific immunity in the salivary gland ; 3) The bridging mechanisms between immunity for the induction of antigen-specific immune responses in salivary glands induced by specific mucosal adjuvants and delivery systems ; 4) Assess the roles of gammadelta T cells in the salivary intranet which bridge innate with acquired immunity ; and 5) Determine how innate gammadelta T cells-CD4 about alphabeta T cells interact for IgA responses in the SMG.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012242-07
Application #
6621930
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Shum, Lillian
Project Start
1997-04-01
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
7
Fiscal Year
2003
Total Cost
$281,300
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
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
Gilbert, Rebekah S; Kobayashi, Ryoki; Sekine, Shinichi et al. (2011) Functional transforming growth factor-? receptor type II expression by CD4+ T cells in Peyer's patches is essential for oral tolerance induction. PLoS One 6:e27501
Baatarjav, Tselmeg; Kataoka, Kosuke; Gilbert, Rebekah S et al. (2011) Mucosal immune features to phosphorylcholine by nasal Flt3 ligand cDNA-based vaccination. Vaccine 29:5747-57
Fukuyama, Yoshiko; King, Janice D; Kataoka, Kosuke et al. (2011) A combination of Flt3 ligand cDNA and CpG oligodeoxynucleotide as nasal adjuvant elicits protective secretory-IgA immunity to Streptococcus pneumoniae in aged mice. J Immunol 186:2454-61

Showing the most recent 10 out of 24 publications