Research Focus: Synthetic Germinal Centers and Microenvironments for B cell Manufacturing.

Following antigen (Ag) exposure, B cells mature and secrete Ag-specific antibodies to prevent or eliminate pathogens as part of the adaptive immune response. This requires in situ priming of B cells and development of a transient sub-anatomical structure, called germinal centers (GCs) inside the secondary lymphoid organs. B cells can contribute to adoptive B cell therapies (ABCT), which are an emerging area of research where B cells can be used as a preventative or therapeutic “drug” that is manufactured ex vivo and then administered to patients for engraftment and antibody-secretion. However, a major obstacle to ABCT is scalable expansion of antigen-specific B cells ex vivo, preferred differentiation to long-lived plasma-like cells, and to maintain cell survival and engraftment in vivo. Inside GCs, B cells proliferate and differentiate into antibody-secreting cells through constant stimulation and ligation of survival factors provided by follicular dendritic cells (FDC) and follicular helper T cells (Tfh). Plasma B cells, which provide long-term immunity, migrate to bone marrow (BM), where they need a different set of survival signals for maturation and long-term maintenance. Thus, for adoptive B cell therapies to be successful, we must overcome two major challenges – (a) Develop scalable and robust manufacturing platforms for generating antibody-secreting, plasma-like B cells from naïve B cell ex vivo; and (b) understand the critical signals that are necessary to mature and maintain plasma B cells in the BM. We aim to develop scalable ex vivo culture systems to expand and differentiate antigen-specific B cells into antibody-secreting plasma-like cells for cell therapies. The overall objectives are to (i) develop a stroma-free material-based synthetic germinal center (sGC) to mediate antigen-specific B cell activation into plasma-like cells and (ii) using a bioengineered human BM-on-a-chip model, determine the role of ex vivo BM niche in the differentiation, survival, and maintenance of ex vivo derived plasma cells. The trainee will master a wide range of engineering and biological techniques, including particle design and characterization, flow cytometry, and microscopy. The proposed research will provide insight into the critical signals needed for B cell activation and plasma cell expansion ex vivo. This research will provide a foundation for future development of scalable manufacturing systems for generating therapeutic B cells.