Antibodies are routinely used as therapeutic agents to fight a wide range of disorders including asthma, blood cancers, breast cancer, arthritis, and transplant rejection. Humoral immunity against infections depends on the germinal center (GC) differentiation process in the B cell follicles of secondary lymphoid organs, such as spleen and lymph nodes. In GCs, B cells rapidly proliferate and somatically mutated high-affinity antibody secreting cells, i.e. plasma cells, are generated from nave B cells in response to T cell-dependent antigen. To date, the scientific community has relied on animal models to generate high-affinity antibodies and discover fundamental knowledge of GC immunology. Yet scientists are far from understanding the extracellular and intracellular factors that contribute to the exuberant pace of the GC reaction and conversion to antibody secreting cells (ASCs). Recent in vivo studies have uncovered crucial signals such as CD40 ligand (CD40L) from T cells, B cell activation factor from follicular dendritic cells, cytokines, and integrin ligands from the surrounding lymphoid niche, that are required for the induction of GCs and selection of high-affinity cells. Developing biomaterials to recapitulate the process of generating high affinity, antigen specific antibodies ex vivo via the GC process could enable more rapid development of antibodies for use in the treatment of a number of chronic diseases. Such tissue models can also be used to improve the mechanistic investigation into signaling and epigenetic mechanisms that regulate GC B cells. The goal of this study is not to recapitulate all aspects of an in vivo model, but rather to generate a model that will inform the natural process in vivo, and also the development antigen-specific ASCs ex vivo.
The specific aims will focus on engineering designer organoids with tunable ligand specificities, understanding the antigen specific immune response, and establish a link between integrin ligand specificity and cell cycle epigenetics of GC reaction.
Antibodies are routinely used as therapeutic agents to fight a wide range of disorders including blood cancer (leukemia, lymphomas, and multiple myelomas), breast cancer, asthma, arthritis, psoriasis, and transplant rejection. The findings of the proposed research plan enable an immune organoid that is capable of controlling the rate and fate of B cell development into antibody producing cells at user controlled rates.
| Purwada, Alberto; Shah, Shivem B; Béguelin, Wendy et al. (2018) Ex vivo synthetic immune tissues with T cell signals for differentiating antigen-specific, high affinity germinal center B cells. Biomaterials : |
| Apoorva, F; Loiben, Alexander M; Shah, Shivem B et al. (2018) How Biophysical Forces Regulate Human B Cell Lymphomas. Cell Rep 23:499-511 |
| Singh, Ankur; Brito, Ilana; Lammerding, Jan (2018) Beyond Tissue Stiffness and Bioadhesivity: Advanced Biomaterials to Model Tumor Microenvironments and Drug Resistance. Trends Cancer 4:281-291 |
