Theses and Dissertations from UMD
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Item Leveraging Biomaterial Properties to Reprogram Immune Function in Autoimmunity(2020) Gosselin, Emily A; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Autoimmune diseases occur when immune cells incorrectly identify and attack the body’s tissues as foreign. In Multiple Sclerosis (MS), the immune system targets myelin, the protective layer that insulates nerves. Current MS therapies reduce disease severity without treating the cause, requiring frequent treatments to slow disease progression. Further, existing therapies cannot differentiate between dysfunctional myelin-reactive inflammatory cells and normal lymphocytes, leaving patients vulnerable to infection. To overcome these limitations, this dissertation investigated biodegradable polymeric microparticles (MPs) co-loaded with myelin peptides and rapamycin, an immunomodulatory signal. Directly injecting these tolerogenic MPs into key immune tissues (e.g. lymph nodes, LNs), induces myelin-specific regulatory immune cells that selectively control myelin-specific inflammation. This work aimed to advance pre-clinical studies and motivate clinical research in two ways: investigating the systemic impact of intra-LN tolerogenic MPs in two MS models, and enhancing MP stability using Chemistry, Manufacturing, and Controls (CMC) considerations. This work showed that across both progressive and relapsing-remitting disease, one tolerogenic intra-LN treatment promoted long-lasting improvements in disease-induced paralysis. Tolerogenic MPs delivered prior to symptom onset promoted tolerance and protected against disease. Treatment at peak disease reversed paralysis and prevented relapse, while treatment during relapse limited disease progression. Strikingly, mice vaccinated against a foreign protein on the same day as intra-LN treatment generated protein-specific T cells and antibodies at similar levels to healthy vaccinated mice, while simultaneously exhibiting significantly reduced paralysis – highlighting the myelin-specific nature of this therapy. While the low dosage requirements of these studies allowed for on-demand preparation, clinical translation requires investigation into manufacturing, preservation, storage, and stability of this immunotherapy. Thus, this dissertation also tested the impact of lyophilization (freeze-drying) and excipients (stabilizing molecules) on MP stability after storage. Lyophilization with low concentrations of excipients significantly improved MP stability and formulation recovery after reconstitution. Storage for 5 months at room temperature did not negatively impact cargo loading, MP size, or biofunctionality. MP formulations with excipients could deactivate inflammatory signaling and restrict myelin-specific immune cell proliferation as well as formulations without excipients. Together, these studies motivate the development of intra-LN delivery of tolerogenic MPs as a potential MS immunotherapy for clinical translation.Item ENGINEERING THE LYMPH NODE MICROENVIRONMENT TO MODULATE ANTIGEN-SPECIFIC T CELL RESPONSE(2019) Gammon, Joshua Marvin; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Vaccines and immunotherapies have provided enormous benefit to human health. However, the development of effective vaccines and immunotherapies for many diseases is hindered by challenges created by the complex pathologies of these targets. For example, in cancer the tumor microenvironment suppresses the function of tumor-specific T cells. In autoimmune diseases, lymphocytes specific for self-antigens attack self-tissue. New technologies providing more sophisticated control over immune response are needed to address these challenges. Lymph nodes (LNs) are tissues where adaptive immune responses develop. Therefore, local delivery of combinations of immune signals is a potential strategy to modulate antigen-specific T cell response for pro-immune or regulatory function. However, application of this idea is hindered since traditional administration routes provide little control over the kinetics, combinations and concentrations with which immune signals are delivered to LNs. Biomaterials have emerged as important tools to overcome these challenges as they provide unique capabilities, including co-delivery, targeting, and controlled release. The research presented here harnesses biomaterials to control immune signals present in LNs to modulate antigen-specific T cell response. In one area, intra-LN injection (i.LN) was used to deposit microparticles (MPs) encapsulating tumor-antigens, adjuvants and immunomodulators to promote tumor-specific central memory T cells. These cells display increased proliferative capacity and resistance to tumor-mediated immunosuppression. MPs encapsulating CpG, an inflammatory adjuvant, and a melanoma antigen potently expanded tumor-specific T cells. MPs delivering low doses of rapamycin – a regulatory immune signal – promoted tumor-specific central memory T cells when co-delivered with the melanoma vaccine. Another important aspect of T cell phenotype which can be modulated for therapeutic benefit is regulatory immune response to control autoimmunity. In this second area, biomaterial-based strategies were used to deliver regulatory immune signals to expand regulatory T cells (TREG) and promote immune tolerance. In one direction, liposomes were designed to deliver regulatory metabolic modulators to bias T cells. In a parallel direction, MPs encapsulating rapamycin and islet self-antigens were designed to promote tolerance in T1D. i.LN delivery of MPs expanded islet-specific TREG and inhibited disease in a mouse model of T1D. Together this work demonstrates potent and modular strategies to therapeutically modulate T cell response.Item Design of Self-Assembling Nanostructures to Promote Immune Tolerance(2018) Hess, Krystina; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)In 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.Item Controlled Delivery of a Glutamate Receptor Modulator to Promote Regulatory T cells and Restrain Autoimmunity(2015) Gammon, Joshua Marvin; Jewell, Christopher M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Autoimmunity occurs when the immune system incorrectly recognizes and attacks self-molecules. Current therapies involve broad immunosuppressants that are not curative and leave patients immunocompromised. Dendritic cells (DCs) are a target for new therapies because DCs influence the differentiation of immune effector cells. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a glutamate receptor enhancer, modulates DC cytokine profiles to polarize T cells toward regulatory phenotypes (TREG ) that are protective in multiple sclerosis (MS). However, PHCCC treatment is limited by poor solubility, a short half-life, and toxicity. We hypothesized that controlled delivery of PHCCC from nanoparticles would alter DC function with reduced treatment frequency. PHCCC nanoparticles attenuated DC activation and promoted TREGs while reducing toxicity 30-fold. In mouse models of MS, these particles delayed disease and reduced severity compared to an equivalent dosing schedule of soluble drug. This outcome demonstrates controlled delivery of metabolic modulators can promote tolerance, suggesting a new route to improve autoimmune therapy.