Dendritic Cells (DCs) are specialized to capture and process antigens in vivo, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules and recognized by T cells. Maturation and subsets allow DCs to control the diverse immune responses. To harness DCs for vaccination, we have made high affinity monoclonal antibodies against more than ten DC surface molecules. We have shown DCs control the quality of immune responses by taking up antigens through different DC-lectins. Our overall long-term goal is the development of novel human vaccines based on in vivo DC-targeting. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, priming of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the magnitude and the quality of mucosal homing effectors. The current objective to determine novel DC-targeting vaccines that prime mucosal homing antibody-secreting plasma cells and polyfunctional high avidity CD8+ T cells with broad specificity with the help from appropriate type of CD4+ T cells. Hypothesis: Antigen-specific mucosal immunity can be efficiently induced by a DC-targeting vaccine composed of a unique combination of a specific anti-DC receptor antibody, antigen, and DC activator.
AIM 1 : To identify a combination of anti-DC fusion protein and DC activator that allows DCs to induce potent antigen-specific mucosal antibody responses in vitro.
AIM 2 : To identify a combination of anti-DC fusion protein and DC activator that allow DCs to induce polyfunctional and mucosal-homing CD8+ T cells in vitro.
AIM 3 : To identify combinations of anti-DC fusion protein and DC activator that induce helper CD4+ T cells for potent mucosal humoral responses and CTL responses. Thus, we will establish an optimal combination(s) of anti-DC fusion proteins and DC activators which potently induce mucosal antibody and/or CTL responses.

Public Health Relevance

These studies will contribute to the overall goal of this U19 center which is to further develop a vaccine platform based on targeting DCs in vivo. Once validated, this platform can be applied to all infectious disease thereby bringing a significant contribution to public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057234-10
Application #
8463988
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$242,013
Indirect Cost
$69,794
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-95
Salabert, Nina; Todorova, Biliana; Martinon, Frédéric et al. (2016) Intradermal injection of an anti-Langerin-HIVGag fusion vaccine targets epidermal Langerhans cells in nonhuman primates and can be tracked in vivo. Eur J Immunol 46:689-700
Kovats, S; Turner, S; Simmons, A et al. (2016) West Nile virus-infected human dendritic cells fail to fully activate invariant natural killer T cells. Clin Exp Immunol 186:214-226
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77
Yin, Wenjie; Gorvel, Laurent; Zurawski, Sandra et al. (2016) Functional Specialty of CD40 and Dendritic Cell Surface Lectins for Exogenous Antigen Presentation to CD8(+) and CD4(+) T Cells. EBioMedicine 5:46-58
Ueno, Hideki; Banchereau, Jacques; Vinuesa, Carola G (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142-52
Schmitt, Nathalie; Ueno, Hideki (2015) Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol 34:130-6
Joo, HyeMee; Upchurch, Katherine; Zhang, Wei et al. (2015) Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization. J Immunol 195:1723-31
Akinbobuyi, Babatope; Byrd, Matthew R; Chang, Charles A et al. (2015) Facile syntheses of functionalized toll-like receptor 7 agonists. Tetrahedron Lett 56:458-460
Trobaugh, Derek; Green, Sharone (2015) Of Mice and Men: Protective and Pathogenic Immune Responses to West Nile virus Infection. Curr Trop Med Rep 2:41-48

Showing the most recent 10 out of 120 publications