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

项目摘要 抗体通常被用作治疗剂来对抗广泛的疾病，包括哮喘、血液病、呼吸道疾病、糖尿病和糖尿病。 癌症、乳腺癌、关节炎和移植排斥。抗感染的体液免疫取决于 次级淋巴器官的B细胞滤泡中的生发中心（GC）分化过程，如 脾脏和淋巴结。在GC中，B细胞快速增殖，体细胞突变的高亲和力抗体 分泌细胞，即浆细胞，是由应答T细胞依赖性抗原的幼稚B细胞产生的。到 迄今为止，科学界一直依赖于动物模型来产生高亲和力抗体， GC免疫学的基础知识。然而，科学家们还远未了解细胞外和 有助于GC反应和转化为抗体的旺盛步伐的细胞内因子 分泌细胞（ASCs）。最近的体内研究发现了关键信号，如CD40配体（CD40L） 来自T细胞的细胞因子、来自滤泡树突细胞的B细胞活化因子、来自淋巴细胞的细胞因子和整合素配体。 周围淋巴生态位，这是诱导GC和选择高亲和力细胞所需的。 开发生物材料以重现产生高亲和力抗原特异性抗体的过程， 通过GC方法在体内的应用能够更快速地开发用于治疗 慢性病的数量。这样的组织模型也可用于改善机理研究 调节GC B细胞的信号传导和表观遗传机制。这项研究的目的不是要概括 体内模型的所有方面，而是生成将告知体内自然过程的模型，以及 也可以离体产生抗原特异性ASC。具体目标将集中在工程设计师 具有可调配体特异性的类器官，了解抗原特异性免疫反应，并建立 整合素配体特异性和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.