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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2023)

Chronic autoimmune disorders collectively affect 5-7% of the global population and are a major public health concern. The prevailing paradigm for autoimmune disease treatment relies on immunosuppression, which can be effective but leaves patients susceptible to opportunistic or serious infections and cancer. Moreover, these therapies are not designed to correct immune dysfunction that underlies autoimmunity. For those that continue to experience disease symptoms, there is an unmet need for therapies that operate via immunoregulation and avoid generalized immunosuppression. A key challenge is that unlike diseases with known etiology, the pathogenesis of autoimmune diseases can be complex. However, a common feature involves hyperactivated immune cells that, left unchecked, can lead to permanent damage of healthy tissue. To this end, a key defect arises from a loss in the number and function of autoimmune-protective cells called regulatory T cells (Treg) that normally prevent immune responses against one’s own cells and tissues. The premise of this dissertation is that enhancing Treg can be harnessed to promote disease-specific immunoregulation without causing generalized immunosuppression. To test the premise, the work reported herein describes the development and applications of biomaterial-based disease modifying agents. Three methods are described. The first method described used an immunomodulatory nanocomplex formulation that differentially modulated immune cell metabolism to enhance Treg over inflammatory T cells. A kinetic model describing Treg enhancement confirmed a strong dependence on the initial T cell population. The second and third methods described demonstrated that the epigenetic modulation of immune cells can strongly influenced the immunophenotypic trajectories of T cells that favor a Treg phenotype. Further, the formulation of a novel sustained biomaterial designed to locally enhance Treg via epigenetic modulation and its application in a model of inflammatory arthritis is reported. Overall, this work paves the way for the systematic design and validation of immunoregulatory biomaterials for the treatment of autoimmune disorders.

    Cover page: Design and Applications of Immunoregulatory Biomaterials in Autoimmune Disease
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2020)
    Regulatory T cells (Tregs) are critical mediators of peripheral immune tolerance. Tregs suppress immune activation against self-antigens and are the focus of cell-based therapies for autoimmune diseases. However, Tregs circulate at a very low frequency in blood, limiting the number of cells that can be isolated by leukapheresis. To effectively expand Tregsex vivo for cell therapy, we report the metabolic modulation of T cells using mono-(6-amino-6-deoxy)-β-cyclodextrin (βCD-NH2) encapsulated rapamycin (Rapa). Encapsulating Rapa in β-cyclodextrin increased its aqueous solubility ∼154-fold and maintained bioactivity for at least 30 days. βCD-NH2-Rapa complexes (CRCs) enriched the fraction of CD4+CD25+FoxP3+ mouse T (mT) cells and human T (hT) cells up to 6-fold and up to 2-fold respectively and suppressed the overall expansion of effector T cells by 5-fold in both species. Combining CRCs and transforming growth factor beta-1 (TGF-β1) synergistically promoted the expansion of CD4+CD25+FoxP3+ T cells. CRCs significantly reduced the fraction of pro-inflammatory interferon-gamma (IFN-γ) expressing CD4+ T cells, suppressing this Th1-associated cytokine while enhancing the fraction of IFN-γ- tumor necrosis factor-alpha (TNF-α) expressing CD4+ T cells. We developed a model using kinetic rate equations to describe the influence of the initial fraction of naïve T cells on the enrichment of Tregsin vitro. The model related the differences in the expansion kinetics of mT and hT cells to their susceptibility for immunophenotypic modulation. CRCs may be an effective and potent means for phenotypic modulation of T cells and the enrichment of Tregsin vitro. Our findings contribute to the development of experimental and analytical techniques for manufacturing Treg based immunotherapies.
      Cover page: Characterization of regulatory T cell expansion for manufacturing cellular immunotherapies
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2019)
      Harnessing an individual's immune cells to mediate antitumor and antiviral responses is a life-saving option for some patients with otherwise intractable forms of cancer and infectious disease. In particular, T-cell-based engineered immune cells are a powerful new class of therapeutics with remarkable efficacy. Clinical experience has helped to define some of the major challenges for reliable, safe, and effective deployment of T-cells against a broad range of diseases. While poised to revolutionize immunotherapy, scalable manufacturing, safety, specificity, and the development of resistance are potential roadblocks in their widespread usage. The development of molecular engineering tools to allow for the direct or indirect engineering of T-cells to enable one to troubleshoot delivery issues, amplify immunomodulatory effects, integrate the synergistic effects of different molecules, and home to the target cells in vivo. In this review, we will analyze thus-far developed cell- and material-based tools for enhancing T-cell therapies, including methods to improve safety and specificity, enhancing efficacy, and overcoming limitations in scalable manufacturing. We summarize the potential of T-cells as immune modulating therapies and the potential future directions for enabling their adoption for a broad range of diseases. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Cells at the Nanoscale.
        Cover page: Applications of molecular engineering in T‐cell‐based immunotherapies
        • Article
        LBL Publications (2002)
          Cover page: Contract and beyond GEMnet status and accomplishments: GSA's energy and maintenance network
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2023)
          Sustained release of vaccine components is a potential method to boost efficacy compared with traditional bolus injection. Here, we show that a biodegradable hyaluronic acid (HA)-scaffold, termed HA cryogel, mediates sustained antigen and adjuvant release in vivo leading to a durable immune response. Delivery from subcutaneously injected HA cryogels was assessed and a formulation which enhanced the immune response while minimizing the inflammation associated with the foreign body response was identified, termed CpG-OVA-HAC2. Dose escalation studies with CpG-OVA-HAC2 demonstrated that both the antibody and T cell responses were dose-dependent and influenced by the competency of neutrophils to perform oxidative burst. In immunodeficient post-hematopoietic stem cell transplanted mice, immunization with CpG-OVA-HAC2 elicited a strong antibody response, three orders of magnitude higher than dose-matched bolus injection. In a melanoma model, CpG-OVA-HAC2 induced dose-responsive prophylactic protection, slowing the tumor growth rate and enhancing overall survival. Upon rechallenge, none of the mice developed new tumors suggesting the development of robust immunological memory and long-lasting protection against repeat infections. CpG-OVA-HAC2 also enhanced survival in mice with established tumors. The results from this work support the potential for CpG-OVA-HAC2 to enhance vaccine delivery.
            Cover page: Biodegradable scaffolds for enhancing vaccine delivery
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2021)
            Inflammation is an essential cytokine-mediated process for generating a neutralizing immune response against pathogens and is generally protective. However, aberrant or excessive production of pro-inflammatory cytokines is associated with uncontrolled local and systemic inflammation, resulting in cell death and often irreversible tissue damage. Uncontrolled inflammation can manifest over timescales spanning hours to years and is primarily dependent on the triggering event. Rapid and potentially lethal increase in cytokine production, or a 'cytokine storm,' develops in hours to days and is associated with cancer cell-based immunotherapies, such as CAR-T cell therapy. On the other hand, some bacterial and viral infections with high microbial replication or highly potent antigens elicit immune responses that result in supraphysiological systemic cytokine concentrations which manifest over days to weeks. Immune dysregulation in autoimmune diseases can lead to chronic cytokine-mediated tissue damage spanning months to years, which often occurs episodically. While the initiating events and cellular participants may differ in these disease processes, many of the cytokines that drive disease progression are shared. For example, upregulation of IL-1, IL-6, IFN-γ, TNF, and GM-CSF frequently coincides with cytokine storm, sepsis, and autoimmune disease. Targeted inhibition of these pro-inflammatory molecules via antagonist monoclonal antibodies has improved clinical outcomes, but the complexity of the underlying immune dysregulation results in high variability. Rather than a "one size fits all" treatment approach, an identification of disease endotypes may permit the development of effective therapeutic strategies that address the contributors of disease progression. Here, we present a literature review of the cytokine-associated etiology of acute and chronic cytokine-mediated tissue damage, describe successes and challenges in developing clinical treatments, and highlight advancements in preclinical therapeutic strategies for mitigating pathological cytokine production.
              Cover page: Triggers, Timescales, and Treatments for Cytokine-Mediated Tissue Damage
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2021)

              Introduction

              Breakthroughs in cancer immunotherapy have spurred interest in the development of vaccines to mediate prophylactic protection and therapeutic efficacy against primary tumors or to prevent relapse. However, immunosuppressive mechanisms employed by cancer cells to generate effective resistance have hampered clinical translation of therapeutic cancer vaccines. To enhance vaccine efficacy, the immunomodulatory properties of cytoreductive therapies could amplify a cancer-specific immune response.

              Areas covered

              Herein, the authors discuss therapeutic cancer vaccines that harness whole cells and antigen-targeted vaccines. First, recent advancements in both autologous and allogeneic whole-cell vaccines and combinations with checkpoint blockade and chemotherapy are reviewed. Next, tumor antigen-targeted vaccines using peptide-based vaccines and DNA-vaccines are discussed. Finally, combination therapies using antigen-targeted vaccines are reviewed.

              Expert opinion

              A deeper understanding of the immunostimulatory properties of cytoreductive therapies has supported their utility in combination therapies involving cancer vaccines as a potential strategy to induce a durable anti-tumor immune response for multiple types of cancers. Based on current evidence, combination therapies may have synergies that depend on the identity of the cytotoxic agent, vaccine target, dosing schedule, and cancer type. Together, these observations suggest that combining cancer vaccines with immunomodulatory cytoreductive therapy is a promising strategy for cancer therapy.
                Cover page: Combining therapeutic vaccines with chemo- and immunotherapies in the treatment of cancer
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2022)
                Despite growing interest in edible seaweeds, there is limited information on seaweed chemical contaminant levels in the Salish Sea. Without this knowledge, health-based consumption advisories can not be determined for consumers that include Tribes and First Nations, Asian and Pacific Islander community members, and recreational harvesters. We measured contaminant concentrations in edible seaweeds (Fucus distichus, F. spiralis, and Nereocystis luetkeana) from 43 locations in the Salish Sea. Metals were analyzed in all samples, and 94 persistent organic pollutants (POPs) (i.e. 40 PCBs, 15 PBDEs, 17 PCDD/Fs, and 22 organochlorine pesticides) and 51 PAHs were analyzed in Fucus spp. We compared concentrations of contaminants to human health-based screening levels calculated from the USEPA and to international limits. We then worked with six focal contaminants that either exceeded screening levels or international limits (Cd, total Hg, Pb, benzo[a]pyrene [BaP], and PCBs) or are of regional interest (total As). USEPA cancer-based screening levels were exceeded in 30 samples for the PCBs and two samples for BaP. Cadmium concentrations did not exceed the USEPA noncancer-based screening level but did exceed international limits at all sites. Lead exceeded international limits at three sites. Because there are no screening levels for total Hg and total As, and to be conservative, we made comparisons to methyl Hg and inorganic As screening levels. All samples were below the methyl Hg and above the inorganic As screening levels. Without knowledge of the As speciation, we cannot assess the health risk associated with the As. While seaweed was the focus, we did not consider contaminant exposure from consuming other foods. Other chemicals, such as contaminants of emerging concern (e.g., PFAS, pharmaceuticals and personal care products), should also be considered. Additionally, although we focused on toxicological aspects, there are cultural and health benefits of seaweed use that may affect consumer choice.
                  Cover page: Chemical contaminant levels in edible seaweeds of the Salish Sea and implications for their consumption
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2020)
                  The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built-in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive-like rapid production of H2 bubbles, providing the necessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.
                    Cover page: Built-In Active Microneedle Patch with Enhanced Autonomous Drug Delivery.
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2023)
                    Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.
                      Cover page: Immune‐responsive biodegradable scaffolds for enhancing neutrophil regeneration
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