Engineered Systems of the Germinal Center and Bone Marrow for Antigen-Specific B Cell Generation and Longevity

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KRAMER-DISSERTATION-2024.pdf (6.2 MB)
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Kramer, Liana
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Wallace H. Coulter Department of Biomedical Engineering
The joint Georgia Tech and Emory department was established in 1997
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https://hdl.handle.net/1853/77691
Abstract
Memory and plasma B cells, which are responsible for maintaining protective levels of antibodies in the serum, are generated following antigen exposure. Due to the crucial roles that B cells play in the immune system, understanding and controlling the function of B cells is important in the context of therapeutic development for vaccines, immunotherapies, and cell therapies. An obstacle to producing prophylactic or therapeutic plasma and memory B cells-based treatments is a poor understanding of the complex cues and microenvironments that lead to the robust expansion of high-affinity, antigen-specific B cells and the development of long-lived plasma cells. Mimicking this complex set of events needed for B cell activation in robust and controllable in vitro platforms could allow for a better understanding of the critical signals that are necessary to mature and maintain B cells. The objectives of this work are to 1) mimic the germinal center (GC) reaction using a biomaterials particle-based platform to mediate antigen-specific B cell activation and 2) model the maturation, maintenance, and dynamics of antibody secreting cells (ASCs) within a supportive bone marrow-on-a chip microniche. In Aim 1, we present a particle based in vitro GC that induces rapid B cell proliferation, efficient induction of the GC reaction, and IgG class-switching in both murine and human cells. We demonstrate the importance of antigen presentation on lipid membranes using liposomes to mimic follicular dendritic cell membrane fragments. In Aim 2, we present a microphyisological human bone marrow model that allows for ASC maturation and use it to study the dynamics and interactions of ASCs with cellular and extracellular matrix components of the bone marrow niche. These results can be leveraged to generate long-lived, high-affinity memory cell populations more effectively and to design strategies to treat conditions where B cell processes are comprised, such as aging, cancers, and autoimmunity.
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2024-04-25
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