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.

项目总结 开发针对SARS-COV-2和流感等新出现感染的疫苗需要增强 了解体内潜在的抗体免疫反应。尽管抗体被用作 治疗剂，可以从融合的杂交瘤模型、动物模型或基因工程中获得，这些 技术不能解释抗体形成的详细免疫学过程，因此，不能 破译或预测宿主与病原体相互作用的结果。对哺乳动物免疫系统的研究已经 长期以来，仅限于体内方法或对有限的供体淋巴组织进行的单一时间点研究，这 通常不允许对细胞内和细胞外过程进行多维空间和时间控制 调节免疫细胞的决策。这是由于淋巴结的复杂性，它有不同的 B和T细胞、基质细胞和抗原提呈细胞的壁龛。当暴露于抗原时，B细胞会经历 一种高度受控的激活过程，称为生发中心(GC)反应，使抗原特异性 抗体分泌细胞。在GC内部，幼稚的B细胞被激活、增殖、迁移、经历 免疫球蛋白类转换，并通过体细胞超突变和T细胞为基础提高其抗原亲和力 选择，产生对特定抗原具有高亲和力的长寿浆细胞。然而，机械论 对GC过程的了解主要来自小鼠淋巴结或2D B细胞培养，而不是 生成真正的GC响应。R21的目标是开发一个免疫芯片平台，该平台(A) 结合淋巴结的关键分子和细胞成分来诱导GC反应并使B细胞 细胞迁移，(B)通过强制亲和成熟过程选择高亲和力的B细胞。免疫芯片 将提供对GC细胞过程的多维控制，允许快速产生免疫疗法， 并作为快速测试平台来确定候选疫苗和免疫原。成功的申请 该项目的实施将有助于快速发现现有和新出现感染的候选疫苗， 包括致命性流感和SARS-CoV-2。