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

基于生物材料的生发中心，用于了解 B 细胞成熟和 B 细胞受体信号传导

基本信息

批准号：
10222176
负责人：
Ankur Singh
金额：
$ 31.61万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-09 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222176
关键词：
Affinity Animal Model Antibodies Antibody Affinity Antibody-Producing Cells Antigens Apoptosis Area Arthritis Asthma B Cell Proliferation B cell differentiation B-Cell Activation B-Cell Development B-Lymphocytes Binding Biocompatible Materials CD40 Ligand Cell Adhesion Cell Cycle Cell Cycle Checkpoint Genes Cell Maturation Cells Chronic Disease Communities Complex Cyclin-Dependent Kinase Inhibitor Development Differentiation Antigens Disease Engineering Enhancers Epigenetic Process Extracellular Matrix Follicular Dendritic Cells Generations Goals Graft Rejection Hematopoietic Neoplasms Histones Homologous Gene Humoral Immunities Immune Immune response Immune signaling Immunization Immunoglobulin-Secreting Cells Immunology Infection Integrin alpha4beta1 Integrins Investigation Kinetics Knockout Mice Knowledge Ligands Link Lymphoid Lymphoid Tissue Lysine Mediating Medicine Methylation Methyltransferase Modeling Multiple Myeloma Mus Mutate Nature Organoids Pathway interactions Phenotype Physiology Plasma Cells Polycomb Polyethylene Glycols Population Process Proliferating Proteins Protocols documentation Psoriatic Arthritis RGD (sequence)Reaction Receptor Signaling Receptors, Antigen, B-Cell Recycling Reporting Research Role Scientist Signal Transduction Specificity Spleen Structure of germinal center of lymph node Surface T-Lymphocyte Therapeutic Agents Time Tissue Engineering Tissue Model Tissues Transgenic Mice Transgenic Organisms Tumor Necrosis Factor Ligand Superfamily Member 6 Work base combinatorial cytokine design experimental study extracellular fighting histone methyltransferase improved in vivo in vivo Model knock-down leukemia/lymphoma lymph nodes malignant breast neoplasm mouse model multidisciplinary response secondary lymphoid organ

项目摘要

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.

项目摘要抗体通常用作抗击多种疾病（包括哮喘，血液）的治疗剂癌症，乳腺癌，关节炎和移植排斥。对感染的体液免疫取决于次生淋巴器官的B细胞福里中的生发中心（GC）分化过程，例如脾脏和淋巴结。在GC中，B细胞迅速增殖和体形突变的高亲和力抗体分泌细胞，即浆细胞是由幼稚的B细胞产生的，响应T细胞依赖性抗原。到日期，科学界依靠动物模型来生成高亲和力抗体并发现 GC免疫学的基本知识。然而，科学家远没有理解细胞外和有助于GC反应的旺盛空间并转化为抗体的细胞内因子分泌细胞（ASC）。最近的体内研究发现了关键信号，例如CD40配体（CD40L）来自T细胞，B细胞活化因子来自卵泡树突状细胞，细胞因子和整联蛋白配体的B细胞活化因子。诱导GC和高亲和力细胞所需的围绕淋巴生态位。开发生物材料以概括产生高亲和力的过程，抗原特异性抗体Ex 通过GC过程的体内可以使抗体的更快开发用于治疗慢性疾病的数量。这样的组织模型也可以用于改善机械研究进入调节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概括体内模型的所有方面还有开发抗原特异性的ASC。具体目标将重点放在工程设计师上具有可调配体规范的类器官，了解抗原特异性免疫反应并建立整联蛋白配体特异性与GC反应的细胞周期表观遗传学之间的联系。