Engineered ImmuneChip Platform to Study B cell Migration and Affinity Maturation

用于研究 B 细胞迁移和亲和力成熟的工程免疫芯片平台

• 批准号: 10206458
• 负责人: Ankur Singh
• 金额: $ 18.14万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-22 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206458
• 关键词: 2019-nCoV; Address; Affinity; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; Avidity; B cell differentiation; B-Cell Antigen Receptor; B-Lymphocytes; Biocompatible Materials; Biomimetics; Cell Communication; Cell Culture Techniques; Cell Cycle Progression; Cell physiology; Cells; Confocal Microscopy; Development; Devices; Encapsulated; Engineering; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Exploratory/Developmental Grant; Exposure to; Flow Cytometry; Follicular Dendritic Cells; Future; Generations; Genetic Engineering; Goals; Haptens; Hybridomas; Hydrogels; Image Cytometry; Immune; Immune response; Immune system; Immunize; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Immunoglobulin-Secreting Cells; Immunologics; Immunotherapeutic agent; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Light; Liquid substance; Lymphoid Tissue; Microfluidics; Modeling; Molecular; Molecular Analysis; Mus; Nature; Organoids; Pattern; Phenotype; Plasma Cells; Process; Proliferating; Reaction; Reporting; Series; Stromal Cells; Structure of germinal center of lymph node; Surface Plasmon Resonance; System; T-Lymphocyte; Techniques; Therapeutic Agents; Time; Tissue Engineering; Tissues; Transgenic Mice; Vaccines; base; cell motility; chemokine; design; extracellular; high reward; high risk; immune function; in vivo; lymph nodes; migration; multidisciplinary; outcome prediction; pathogen; rapid testing; response; transcriptome; two-photon; vaccine candidate; vaccine discovery

PROJECT SUMMARY Developing vaccines against emerging infections such as SARS-COV-2 and influenza requires an enhanced understanding of the underlying antibody immune response in the body. Although antibodies, used as therapeutic agents, can be derived from fused hybridoma models, animal models, or genetic engineering, these techniques cannot explain the detailed immunological process of antibody formation and therefore, cannot decipher or predict outcomes of host-pathogen interactions. The study of the mammalian immune system has long been limited to in vivo approaches or single time point studies with limited donor lymphoid tissues, which often do not allow multidimensional spatial and temporal control of intracellular and extracellular processes that regulate the decisions of immune cells. This is attributable to the complexity of lymph nodes, which have distinct niches of B and T cells, stromal cells, and antigen-presenting cells. When exposed to antigens, B cells undergo a highly controlled activation process, called the germinal center (GC) reaction, which makes antigen-specific antibody-secreting cells. Inside GCs, naïve B cells become activated, proliferate, migrate, undergo immunoglobulin class switching, and increase their antigen affinity by somatic hypermutation and T cell-based selection, yielding long-lived plasma cell with high affinity for specific antigens. However, the mechanistic understanding of the GC process is largely derived from mouse lymph nodes or 2D B cell cultures, that do not generate a bona fide GC response. The goal of this R21 is to develop an ImmuneChip platform that (A) incorporates key molecular and cellular components of the lymph nodes to induce GC reactions and enable B cell migration, (B) selects for high-affinity B cells through a forced affinity maturation process. The ImmuneChip will provide multidimensional control of cellular processes in GCs, allow rapid generation of immune therapeutics, and serve as a rapid testing platform to identify candidate vaccines and immunogens. The successful application of this project will facilitate the rapid discovery of vaccine candidates for existing and emerging infections, including lethal influenza and SARS-CoV-2.

项目摘要 开发针对SARS-COV-2等新兴感染的疫苗，并影响增强 了解体内潜在抗体免疫反应。虽然抗体被用作 可以从融合的杂交瘤模型，动物模型或基因工程中得出治疗剂，这些 技术无法解释抗体形成的详细免疫学过程，因此不能 破译或预测宿主 - 病原体相互作用的结果。哺乳动物免疫系统的研究具有 长期以来一直限于体内方法或具有有限的供体淋巴组织的单个时间点研究， 通常不允许多维空间和临时控制细胞内和细胞外过程 调节免疫细胞的决策。这归因于具有不同的淋巴结的复杂性 B和T细胞，基质细胞和抗原呈递细胞的壁ni。当暴露于抗原时，B细胞会经历 高度控制的激活过程，称为生发中心（GC）反应，该反应使抗原特异性 分泌细胞。在GC内部，幼稚的B细胞被激活，增殖，迁移，经历 免疫球蛋白类切换，并通过躯体过度和基于T细胞的抗原亲和力增加其抗原亲和力 选择，产生长寿命的浆细胞，对特定抗原具有高亲和力。但是，机械 对GC过程的理解主要来自小鼠淋巴结或2D B细胞培养物，而不是 产生真正的GC响应。 R21的目标是开发一个疫苗平台（a） 结合淋巴结的关键分子和细胞成分，以诱导GC反应并启用B 细胞迁移，（b）通过强制亲和力成熟过程为高亲和力B细胞选择。侵犯 将提供对GC中细胞过程的多维控制，允许快速生成免疫治疗， 并用作识别候选疫苗和免疫原的快速测试平台。成功的应用程序 该项目将有助于快速发现候选疫苗的现有感染和新兴感染， 包括致命的影响力和SARS-COV-2。