Immune modulation by synthetic multivalent antigens
Author(s)Alam, Mohammad Murshid.
Massachusetts Institute of Technology. Department of Chemistry.
Laura L. Kiessling.
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Modulating immunity by delivering antigens that target antigen presenting cells (APC) is a promising approach for vaccine design. Cell surface receptors of APCs capture antigen for processing and presentation and induce signaling for immune activation. The antigen's structural properties including size, valency, and conjugation strategy can also play key roles in immune modulation. We therefore targeted APCs such as dendritic cells (DCs) and B cells to shape cellular and humoral immunity, respectively, using systematically designed synthetic multivalent antigens. DC-SIGN is a C-type lectin receptor expressed on DCs that recognizes highly mannosylated glycans. It facilitates pathogen recognition and modulate immune response. Herein, we engineered a bacteriophage Q[beta] virus-like particle (VLP) with a multivalent display of mannoside ligands and identified that, high-density display of a phenymannoside enhances VLP uptake by DCs and promotes efficient trafficking to endosomes.The particle also induces proinflammatory cytokine expression and generates a ThI-type immune response in vivo, highlighting its utility as vaccine vehicles to induce cellular immunity. We also investigated the effects that physical properties of antigens have on the fate of DC-SIGN-mediated internalization. We generated soluble and particulate glycopolymers displaying multiple copies of phenylmannoside and showed that particulate antigens traffic to the non-endosomal, surface-accessible compartments where HIV-1 traffics. These particulate antigens also elicited responses associated with HIV-induced DC-SIGN signaling, including expression of cytokines and activation of Raf-1. These results underscore the significance of antigen structure in developing synthetic vaccines. Protective immunity towards extracellular pathogens is mediated by an effective antibody response.To determine structural features of the epitope on antibody responses in vivo, we used synthetic polymers functionalized with defined B- and T-cell epitopes. The T-cell epitope was conjugated with a protease-sensitive linker to facilitate antigen presentation. This design induced a variety of immune responses in mice such as robust IgG antibody, antibody secreting cell, and helper T-cell response. We found that such responses are stronger for polymers that display a high number of T-cell epitopes compared with polymers that display a low copy number of T-cell epitopes. These findings provide insight into the key criteria for conjugate vaccine design against weak immunogens such as carbohydrates.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 2020Cataloged from the PDF of thesis.Includes bibliographical references.
DepartmentMassachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology