Mucosal Macrophages and Tertiary Lymphoid Structures in IBD

IBD 中的粘膜巨噬细胞和三级淋巴结构

基本信息

批准号：
10605344
负责人：
Milena Bogunovic
金额：
$ 54.7万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-16 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10605344
关键词：
Affect Anti-Tumor Necrosis Factor Therapy Antigen Presentation Antigen-Presenting Cells Automobile Driving B-Cell Activation Biological Products Cells Chronic Clinical Colitis Colon Communication Crohn&apos s disease Cytokine Network Pathway Data Dendritic Cells Development Epithelial Cells Genetic Genetic Transcription Goals Heterogeneity Human Immune Immune response Immunity Immunoglobulin A Immunoglobulin G Incidence Infectious colitis Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-10 Interleukin-4 Intestinal Mucosa Intestines Lesion Lymphoid Macrophage Mediator Modeling Mononuclear Mucous Membrane Mus Outcome Pathogenesis Pathogenicity Pathologic Patients Phagocytes Play Prevalence Production Publishing Regulation Resistance Role Salmonella Signal Transduction Stromal Cells Structure T cell differentiation T-Lymphocyte TNF gene Testing Time Transgenic Mice Tumor Necrosis Factor Receptor Ulcerative Colitis dimensional analysis insight mouse model murine colitis novel pathobiont pathogen potential biomarker prevent response salmonella colitis spatiotemporal tertiary lymphoid organ therapeutic target

项目摘要

The incidence and prevalence of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), are increasing worldwide, and the treatment options for IBD are still limited for a large number of patients despite the development of targeted biologics. A mechanistic model of pathogenic communication among immune, stromal and epithelial cells controlled by elaborate cytokine networks that underlies pathogenesis of inflammatory bowel disease (IBD) has been proposed. The next critical step is to establish the spatiotemporal organization of this abnormal immune response. Tertiary lymphoid structures (TLS) are ectopic disorganized lymphoid aggregates found around intestinal inflammatory lesions in patients with CD and UC, possibly in response to persisting pathobionts that breach intestinal mucosa. TLS are recognized as a pathologic hallmark in IBD, however, their precise cellular composition and mechanistic contribution to intestinal immunity and pathogenesis of IBD are largely unknown. The overall goal of this proposal is to unravel the mechanisms that drive TLS formation and elucidate their function in mouse models of colitis relevant to IBD Mononuclear phagocytes (MNPs) that comprise dendritic cell (DC) and macrophage (M) subsets are an important constituent of TLS. In a model of Salmonella colitis, we identified a subset of mucosa-resident (CX3CR1hi) Ms that functions as an antigen-presenting cell driving TLS formation and a Salmonella-specific T cell-dependent IgA response in TLS. We found that TLS play a protective role in Salmonella colitis by restricting systemic pathogen dissemination, but under conditions of chronic inflammation observed in IBD, TLS are likely to acquire a proinflammatory role. Such conversion of TLS function may occur via promotion of TLS-associated pathogenic T cell differentiation and proinflammatory IgG instead of IgA responses as suggested by recent single cell transcriptional analyses of human IBD. Our overall hypothesis is that a key step in the pathogenesis of IBD is dysregulation of CX3CR1hi Ms, and that such dysregulated Ms promote IBD by driving the development of pathogenic TLS that produce T-cell dependent IgG instead of IgA. We will test our hypothesis in three specific aims. Aim 1 will determine the role of antigen-presentation and B cell activation by CX3CR1hi Ms in the development of pathogenic TLS; and Aim 2 will establish the role of TNF signaling in CX3CR1hi Ms in the regulation of TLS function. If successful, the study will provide novel insight into the pathogenesis of IBD and identify potential biomarkers and therapeutic targets (e.g., CX3CR1hi M-derived mediators) associated with TLS in IBD.

包括克罗恩病 (CD) 和溃疡性结肠炎 (UC) 在内的炎症性肠病 (IBD) 的发病率和患病率在全球范围内不断增加，尽管已经开发出针对性的治疗方法，但对于大量患者来说，IBD 的治疗选择仍然有限。已经提出了由复杂的细胞因子网络控制的免疫细胞、基质细胞和上皮细胞之间的致病通讯的机制模型，该网络是炎症性肠病（IBD）发病机制的基础。这种异常免疫反应的时空组织是 CD 和 UC 患者肠道炎症病变周围发现的异位紊乱淋巴聚集体，可能是对破坏肠粘膜的持续病原体的反应，TLS 被认为是一种病理标志。然而，IBD 的精确细胞组成以及对肠道免疫和 IBD 发病机制的机制贡献在很大程度上尚不清楚。该提案的总体目标是揭示驱动机制。 TLS 的形成并阐明其在与 IBD 相关的小鼠结肠炎模型中的功能包含树突细胞 (DC) 和巨噬细胞 (M) 亚群的单核吞噬细胞 (MNP) 是 TLS 的重要组成部分。粘膜驻留 (CX3CR1hi) Ms，作为抗原呈递细胞驱动 TLS 形成和沙门氏菌特异性 T 细胞依赖性 IgA 反应我们发现 TLS 通过限制全身性病原体传播在沙门氏菌结肠炎中发挥保护作用，但在 IBD 中观察到的慢性炎症条件下，TLS 可能通过促进 TLS- 获得促炎作用。最近对人类 IBD 的单细胞转录分析表明，与致病性 T 细胞分化和促炎 IgG 而不是 IgA 反应相关。我们的总体假设是 IBD 发病机制的关键步骤是 IBD 的失调。 CX3CR1hi Ms，并且这种失调的 Ms 通过驱动产生 T 细胞依赖性 IgG 而不是 IgA 的致病性 TLS 的发展来促进 IBD。我们将在三个特定目标中检验我们的假设，目标 1 将确定抗原呈递和 B 的作用。 CX3CR1hi Ms 的细胞激活在致病性 TLS 的发展中；如果成功，该研究将确定 CX3CR1hi Ms 中 TNF 信号传导在 TLS 功能调节中的作用。将提供对 IBD 发病机制的新见解，并确定与 IBD 中 TLS 相关的潜在生物标志物和治疗靶点（例如 CX3CR1hi M 衍生介质）。