Design of Self-Assembling Nanostructures to Promote Immune Tolerance

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dc.contributor.advisorJewell, Christopher Men_US
dc.contributor.authorHess, Krystinaen_US
dc.contributor.departmentBioengineeringen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2018-09-13T05:43:52Z
dc.date.available2018-09-13T05:43:52Z
dc.date.issued2018en_US
dc.description.abstractIn autoimmune diseases, which affect more than 23 million Americans, the immune system mistakenly attacks healthy tissue. This occurs when the process that normally controls self-reactive inflammatory cells (i.e. tolerance) fails. In multiple sclerosis (MS), the myelin sheath, which insulates nerves, is recognized as a foreign antigen. Demyelination by immune cells results in serious symptoms of neurodegeneration. Current treatments for MS are not curative, but rather manage symptoms by broadly suppressing the immune system, leaving patients unable to fight infection. New therapies that are more specific and effective could greatly improve the quality of life for patients. Biomaterials offer specific advantages for generating antigen-specific tolerance, such as cargo protection, targeted delivery, and controlled release of signals. Additionally, recent reports demonstrate that materials themselves can be intrinsically immunogenic. Two promising biomaterials-based strategies for combating autoimmunity involve: 1) delivery of self-antigen with a regulatory molecule or 2) delivery of self-antigen alone. Aim 1 of this dissertation focuses on the first strategy, creating a novel delivery system for myelin peptide and GpG, an immunomodulatory oligonucleotide. This approach involves electrostatic self-assembly of the two immune signals, eliminating the need for a carrier that could exacerbate inflammation, while still offering attractive features of biomaterials, such as co-delivery. The goal is for immune cells to encounter both signals simultaneously, biasing the response towards tolerance. This work represents the first studies using self-assembled materials to target toll-like receptor signaling, recently shown to be implicated in many autoimmune diseases. Aim 2 of this dissertation is based on the second strategy above, which relies on evidence that changing the trafficking and processing of a self-antigen can impact the development of inflammation or tolerance. Quantum dots, NPs that are intrinsically fluorescent and rapidly drain to lymph nodes, can be decorated with a large and controllable number of myelin peptides. These key features of QDs were exploited to reveal that parameters of self-antigen display (i.e. dose, density) impact biodistribution and immune cell uptake, and are directly correlated to the level of tolerance induced. Together, the described nanotechnologies offer opportunities to probe important questions towards the design of antigen-specific therapies.en_US
dc.identifierhttps://doi.org/10.13016/M2DR2PC79
dc.identifier.urihttp://hdl.handle.net/1903/21369
dc.language.isoenen_US
dc.subject.pqcontrolledBiomedical engineeringen_US
dc.subject.pqcontrolledNanotechnologyen_US
dc.subject.pqcontrolledMaterials Scienceen_US
dc.subject.pquncontrolledImmunologyen_US
dc.subject.pquncontrolledImmunotherapyen_US
dc.subject.pquncontrolledNanoparticleen_US
dc.subject.pquncontrolledPolyplexen_US
dc.subject.pquncontrolledQuantum dotsen_US
dc.subject.pquncontrolledToleranceen_US
dc.titleDesign of Self-Assembling Nanostructures to Promote Immune Toleranceen_US
dc.typeDissertationen_US

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