KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Determining Cellular and Molecular Mechanisms of Multivalent Soluble Antigen Arrays that Contribute to Therapeutic Efficacy Against a Murine Model of Multiple Sclerosis

    Thumbnail
    View/Open
    Hartwell_ku_0099D_15053_DATA_1.pdf (48.92Mb)
    Issue Date
    2016-12-31
    Author
    Hartwell, Brittany
    Publisher
    University of Kansas
    Format
    193 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Bioengineering
    Rights
    Copyright held by the author.
    Metadata
    Show full item record
    Abstract
    A pressing need exists for antigen-specific immunotherapies (ASIT) that induce selective tolerance in autoimmune disease while avoiding deleterious global immunosuppression. Multivalent soluble antigen arrays (SAgAPLP:LABL), consisting of a hyaluronic acid (HA) linear polymer backbone co-grafted with multiple copies of autoantigen (PLP) and cell adhesion inhibitor (LABL) peptides, are designed to induce tolerance to a specific multiple sclerosis (MS) autoantigen. Previous in vivo studies established that SAgAPLP:LABL was therapeutic in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. This dissertation sought to elucidate SAgA therapeutic cellular mechanisms while identifying therapeutic molecular properties. In Chapter 2, the role of two-signal co-delivery was explored by evaluating EAE in vivo results in conjunction with in silico molecular dynamics simulations and nanomaterial properties for various covalent and physical combinations of HA, PLP, and LABL. We found that co-delivery of both primary autoantigen and secondary inhibitory signal was necessary for therapeutic efficacy against EAE. In Chapters 3 and 4, the SAgAPLP:LABL cellular mechanism was investigated in a model B cell system by evaluating binding, specificity, and signaling modulation in vitro. Here, we developed click-conjugated cSAgAPLP:LABL which, unlike SAgAPLP:LABL, employed a non-hydrolyzable linker chemistry to conjugate PLP and LABL to HA. cSAgAPLP:LABL exhibited significantly enhanced in vivo efficacy compared to hydrolyzable SAgAPLP:LABL. We found that cSAgAPLP:LABL acted through high avidity, antigen-specific B cell binding, targeting the B cell receptor (BCR) to dampen BCR-mediated signaling. Our conclusions point to induction of antigen-specific B cell anergy as the cSAgAPLP:LABL therapeutic mechanism and present a promising option for ASIT.
    URI
    http://hdl.handle.net/1808/24140
    Collections
    • Engineering Dissertations and Theses [1055]
    • Dissertations [4473]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps