Theses and Dissertations from UMD

Permanent URI for this communityhttp://hdl.handle.net/1903/2

New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM

More information is available at Theses and Dissertations at University of Maryland Libraries.

Browse

Filters

2009 - 200912010 - 20181

Settings

Subject: search.filters.subject.FcRn

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    MUCOSAL DELIVERY OF INFLUENZA VACCINE ANTIGENS
    (2018) Park Ochsner, Susan Soo; Zhu, Xiaoping; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Most pathogens infect humans and animals at mucosal surfaces, yet few mucosal vaccines are available to provide protection at these sites. Though influenza virus initiates its infection in the respiratory mucosal epithelium, currently approved influenza vaccines are administered by parenteral routes, which do not offer effective respiratory immunity. A successful mucosal influenza vaccine should induce both local and systemic immunity, however, the respiratory epithelium is an imposing barrier that prevents vaccine antigens to effectively traverse the airway. The neonatal Fc receptor (FcRn) mediates transport of IgG across the epithelial cell monolayer lining mucosal surfaces. To exploit this antibody transfer pathway for antigen delivery, I produced a soluble fusion protein that fused the monomeric Fc portion of IgG to an influenza hemagglutinin (HA) antigen harboring the T4 fibritin trimerization domain. Intranasal innoculation of the HA-Fc protein along with CpG adjuvant induced high levels of durable mucosal and systemic adaptive immune responses and, importantly, generation of lung-resident memory T cells. FcRn-dependent antigen delivery was corroborated when substantial protection characterized by significantly increased survival and reduced pulmonary pathology was observed in the HA-Fc-immunized wild-type (wt) mice. In contrast, control groups of wt and FcRn-deficient mice immunized with HA-Fc, a mutant version of HA-Fc that lacks FcRn binding capacity, HA alone, or PBS, experienced substantial morbidity, mortality, and lung damage. As the influenza nucleoprotein (NP) is highly conserved among strains, it is an attractive vaccine target. Thus I produced soluble NP-Fc fusion proteins as potential influenza vaccines. The preliminary study demonstrated that intranasal immunization of NP-Fc with CpG resulted in FcRn-mediated delivery of NP-Fc protein across the respiratory barrier and the induction of high levels of antibody titer compared to groups of control mice. Immunization with NP-Fc may be further explored for developing a universal mucosal influenza vaccine. Taken together, for the first time, my results prove that FcRn can effectively deliver an influenza antigen across the respiratory epithelial barrier, providing substantial protection against lethal respiratory infection. This study further suggests FcRn-mediated mucosal vaccination could be used to deliver a universal influenza vaccine antigen or protective antigens from other common respiratory pathogens.
  • Thumbnail Image
    Item
    THE FUNCTIONAL REGULATION OF FCRN EXPRESSION AND FCRN-MEDIATED ANTIGEN PRESENTATION
    (2009) Liu, Xindong; Zhu, Xiaoping; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    The neonatal Fc receptor for IgG (FcRn), a major histocompatibility complex (MHC) class I-related molecule, plays an important role in IgG transport and protection. The transport of IgG across epithelial and endothelial barriers and the IgG homeostasis maintained by FcRn contributes to the effective humoral immunity. Thus, the level of FcRn itself will affect the IgG-associated immune responses. Although FcRn is expressed in a variety of tissues and cell types, the extent to which FcRn expression is regulated by immunological and inflammatory events remains unknown.I showed here that FcRn was up-regulated by the stimulation of inflammatory cytokines or Toll-like receptor ligands in human peripheral blood mononuclear cell (PBMC) and THP-1 cell line. By chromatin immunoprecipitation, I identified three NF-κB binding sites within introns 2 and 4 of the human FcRn gene. These intronic binding sites boost FcRn transcription activities through looping with the promoter region. In contrast, FcRn expression was down-regulated by Th1 cytokine IFN-γ, and the down-regulation of FcRn was not caused by apoptosis or the instability of FcRn mRNA. It has been demonstrated that IFN-γ activated STAT1 bound with GAS sequence in human FcRn promoter, and which blocked the transcriptional machinery. Fc gamma receptors (FcγRs) expressed in macrophages (MФ) and dendritic cells (DCs) can mediate antigen presentation in both MHC class II and MHC class I pathways. We tested here the role for FcRn in antigen presentation of IgG-restricted Immune complexes (ICs). It was observed that the expression of FcRn in MФ, but not in DC enhanced the phagosomal ICs antigen presentation to CD4 T cells. A low pH value in phgosome of MФ facilitated FcRn binding to ICs, stabilizing the antigens and promoting the efficient MHC II-peptide assembly. However, the alkalized phagosomes in DC failed FcRn to enhance the antigen presentation of ICs.