Browsing by Author "Gammon, Joshua Marvin"

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    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.
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    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.