Biomaterials-based Germinal Center Niches for Understanding the B Cell Maturation and B cell receptor signaling

项目总结 抗体通常被用作治疗药物，用于治疗包括哮喘、血液等在内的多种疾病。 癌症、乳腺癌、关节炎和移植排斥反应。对感染的体液免疫取决于 次级淋巴器官B细胞滤泡的生发中心(GC)分化过程，如 脾和淋巴结。在GC中，B细胞迅速增殖和体细胞突变的高亲和力抗体 分泌细胞，即浆细胞，是由幼稚的B细胞对T细胞依赖的抗原做出反应而产生的。至 迄今为止，科学界一直依赖动物模型来产生高亲和力抗体并发现 GC免疫学基础知识。然而，科学家们还远远不能理解细胞外和 促进GC反应和转化为抗体的活跃速度的细胞内因素 分泌细胞(ASC)。最近的体内研究发现了关键信号，如CD40配体(CD40L) 来自T细胞、来自滤泡树突状细胞的B细胞激活因子、来自 周围的淋巴小龛，这是诱导GC和选择高亲和力细胞所必需的。 开发生物材料来概括产生高亲和力、抗原特异性抗体的过程 体内通过GC过程可以更快地开发抗体用于治疗 慢性病的数量。这样的组织模型也可以用来改进机制研究 涉及调控GC B细胞的信号和表观遗传机制。这项研究的目的不是重述 体内模型的所有方面，而是生成一个将告知体内自然过程的模型，以及 也可在体外发育抗原特异性的ASCs。具体目标将集中在工程设计师身上 具有可调节配基特异性的有机化合物，了解抗原特异性免疫反应，并建立 整合素配体特异性与GC反应的细胞周期表观遗传学之间的联系。

PROJECT SUMMARY 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 naïve 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.