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.
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.
|Todorova, Biliana; Salabert, Nina; Tricot, Sabine et al. (2017) Fibered Confocal Fluorescence Microscopy for the Noninvasive Imaging of Langerhans Cells in Macaques. Contrast Media Mol Imaging 2017:3127908|
|Athale, Shruti; Banchereau, Romain; Thompson-Snipes, LuAnn et al. (2017) Influenza vaccines differentially regulate the interferon response in human dendritic cell subsets. Sci Transl Med 9:|
|Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80|
|Silvin, Aymeric; Yu, Chun I; Lahaye, Xavier et al. (2017) Constitutive resistance to viral infection in human CD141+ dendritic cells. Sci Immunol 2:|
|Yoshimatsu, Gumpei; Kunnathodi, Faisal; Saravanan, Prathab Balaji et al. (2017) Pancreatic ?-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation. Diabetes 66:2857-2867|
|Raymond, Donald D; Stewart, Shaun M; Lee, Jiwon et al. (2016) Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain. Nat Med 22:1465-1469|
|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|
|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|
|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 16:1082-1095|
|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|
Showing the most recent 10 out of 128 publications