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Modeling immunity with a hybrid lymph node tissue-chip

使用混合淋巴结组织芯片模拟免疫

基本信息

批准号：
10059169
负责人：
Rebecca R Pompano
金额：
$ 45.13万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-20 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10059169
关键词：
Acute Affect Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Antigens Autoimmunity Biodistribution Biological Models Biological Process Biomedical Research Brain Buffers Caliber Cell Communication Cell Culture Techniques Cells Chemistry Chronic Clinical Coupled Development Devices Disease Drug Targeting Event Experimental Models Gases Goals Hour Human Hybrids Immune response Immune system Immunity Immunology Immunotherapy In Vitro Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Label Lateral Liquid substance Location Lymph Node Tissue Malignant Neoplasms Manuals Measures Membrane Metabolic Methods Microfluidics Modeling Movement Multiple Sclerosis Mus Physiologic pulse Population Production Publishing Research Research Personnel Resolution Response to stimulus physiology Rest Rheumatoid Arthritis Role Signal Transduction Signaling Protein Slice Stimulus Stream Suspensions System Systems Analysis TNF gene TNFRSF1A gene Technology Testing Time Tissue Microarray Tissue Sample Tissue Slice Technology Tissues Tonsil Vaccines Work adaptive immunity behavioral response cell motility chronic inflammatory disease cytokine design experimental study extracellular fighting human tissue improved in vivo in vivo Model inflammatory marker innovation interest lymph nodes macromolecule middle age nanoparticle novel novel therapeutics preservation prevent response therapy design tool tumor tumor necrosis factor-alpha inhibitor young adult

项目摘要

PROJECT SUMMARY/ABSTRACT Local interactions in the immune system determine whether an immune response is protective or destructive, fighting infection or initiating autoimmunity. Adaptive immunity begins in the lymph node (LN), a highly organized and dynamic tissue. Currently, it is difficult to parse the role of inflammatory mediators or rationally design therapies for chronic inflammatory disease such as artherosclerosis, rheumatoid arthritis and multiple sclerosis, which together affect 5 – 7% of the Western population. We hypothesize that analyzing local responses ex vivo in intact tissue will provide information not easily obtained from current methods (in vitro/in vivo). Such experiments require new tools to analyze dynamics in the immune system, which we develop by combining expertise in bioanalytical chemistry, microfluidics, and immunology. In this project, we will develop a novel ex vivo model of immunity, using a hybrid of microfluidic culture and LN slices. In Aim 1, we will establish long-term culture coupled with analysis methods for live murine and human LN slices. Slice culture offers the advantage of preservation of the extracellular microenvironment and any matrix-bound signals. We will optimize long-term culture (7-21 days) for murine LN slices and human tonsil slices to maintain high viability, low cellular activation markers at rest, and ability to respond to inflammatory and antigen-specific stimuli. In Aim 2, we will develop a novel microfluidic system for on-demand local stimulation of LN slices. We will improve the spatial resolution of our previously developed device, to target clusters 2 – 10 cells in diameter (20 – 100 μm lateral resolution) using short- and long-term stimulation. We will also enable on-demand selection of delivery zone by using a mobile port, making the whole tissue accessible with minimal handling. In Aim 3, we will validate the hybrid microfluidic-tissue slice system for analysis of inflammatory responses and anti-inflammatory therapies. We will compare the inflammatory response to a pro-inflammatory cytokine, TNF-α, in slices versus cell cultures and in vivo systems. Finally, we will test the extent to which the model provides new information to guide immunotherapy, by using the hybrid tissue-chip system with mouse and human tissue to compare the effects of competing TNF-α inhibitors (anti-TNF-α monoclonals or soluble TNF-α receptor). Combining local microfluidic stimulation with tissue slice technology produces the first experimental platform for analysis of spatially organized signaling and cell-cell interactions in live LN tissue. This innovative platform will advance both basic and translational biomedical research: locally delivered cytokines will serve as a much-needed model of acute or chronic inflammation, and locally delivered immunotherapies will guide the design of targeted drug-loaded nanoparticles. This technology is broadly applicable for a host of inflammatory diseases, including rheumatoid arthritis, Chron’s disease, multiple sclerosis, Alzheimer’s disease, and cancer.

项目总结/文摘