GALT mediated protection against CNS demyelination: Role of commensal bacteria

GALT 介导的中枢神经系统脱髓鞘保护：共生细菌的作用

基本信息

批准号：
8484553
负责人：
LLOYD H KASPER
金额：
$ 27.65万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8484553
关键词：
Address Adoptive Transfer Animal Model Antibiotics Antigens Attention Autoimmune Process B-Lymphocytes Bacterial Antigens Bacterial Polysaccharides Bacteroides fragilis Biologic Characteristic Blood capillaries Brain CD19 gene Cells Cervical Chronic Data Demyelinating Diseases Demyelinations Dendritic Cells Dermal Development Disease Distal Down-Regulation Equilibrium Evaluation Experimental Autoimmune Encephalomyelitis Experimental Models Genes Genetically Engineered Mouse Gut associated lymphoid tissue Homeostasis Human Immigration Immune Immunity Immunization Immunologics In Vitro Inflammation Inflammatory Integrins Interleukin-10 Interleukin-17 Intestines Ligands Ligation Lymphocyte Lymphoid Tissue Mediating Microarray Analysis Migration Assay Multiple Sclerosis Mus Neuraxis Oral Oral Administration Pathway interactions Pattern Peripheral Phase Phenotype Polysaccharides Population Predisposition Preparation Probiotics Process Regulation Regulatory T-Lymphocyte Role Severities Signal Transduction Small Inducible Cytokine A3 Specificity Spinal Cord T-Cell Activation T-Lymphocyte TLR2 gene Therapeutic Tissues alternative treatment capillary chemokine commensal microbes gut microbiota gut microflora high risk immunoregulation in vivo innovation lymph nodes microbiome migration monolayer novel prophylactic response trafficking

项目摘要

DESCRIPTION (provided by applicant): Recent studies have revealed the importance of the gut associated lymphoid tissue (GALT) and its interaction with gut commensal bacterial population in the balance of peripheral immunity. We have shown that modifying bacterial populations of the gut can protect against EAE, the experimental model of human multiple sclerosis. Prophylactic and therapeutic oral administration of a highly purified, structurally characterized preparation of the bacterial antigen, polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis can protect against EAE in an IL-10 dependent mechanism. Of note, was a significant increase in both CD103+CD11Chigh GALT derived DC and FoxP3+Treg cells with concurrent downregulation of IL-17 in the CLN of protected mice, when compared to untreated controls. We hypothesize that specific gut commensal antigens, in particular capsular polysaccharide A (PSA) of the human commensal bacteria B. fragilis, when administered per os can protect against CNS demyelinating disease. Protection is mediated via TLR-2 ligation of mucosal DC or B cell populations that are polarized and migrate to the CNS and associated lymphoid tissue whereupon they induce disease-modifying regulatory T cells that control inflammation and demyelination. The specific aims are: 1) to identify and phenotype the APC associated with PSA immunization in EAE mice, 2) to identify the specific molecules involved in the migration and trafficking by PSA-associated APCs as well as T/B cells to the brain/spinal cord and CNS associated lymphoid tissues and 3) to determine the requirement of TLR2 in the induction of CD39+/- Tregs and B cells by PSA in the CNS and its associated lymphoid tissue. The innovation of this proposal is two-fold. First, it provides novel information on the immune interplay between commensal activated GALT and regulation of CNS inflammatory demyelination and second puts forth a novel probiotic approach as a potential therapeutic against this chronic debilitating disease with broad implications on the treatment of MS and other autoimmune conditions.

描述（由申请人提供）：最近的研究揭示了肠道相关的淋巴组织（GALT）的重要性及其与肠道分子细菌种群的相互作用在外周免疫平衡中的重要性。我们已经表明，修饰肠道的细菌种群可以预防人类多发性硬化症的实验模型EAE。高度纯化的结构表征制备细菌抗原，多糖A（PSA）的预防性和治疗性口服，源自人类共同细菌的fragilis可以在IL-10依赖机制中预防EAE。值得注意的是，与未经处理的对照相比，在受保护小鼠的CLN中，CD103+CD11chigh Galt衍生的DC和Foxp3+Treg细胞都显着增加IL-17。我们假设特定的肠道共生抗原，特别是人类共生细菌的囊囊多糖A（PSA）。通过TLR-2连接粘膜直流或B细胞群的介导，这些粘膜DC或B细胞种群偏振并迁移到中枢神经系统和相关的淋巴组织，从而诱导控制疾病的调节性T细胞，以控制炎症和脱髓鞘。具体目的是：1）识别和表型与EAE小鼠中与PSA免疫相关的APC，2）确定与PSA相关的APC以及T/B细胞在脑/脊髓和CN相关的淋巴机和3）中的特定分子以及与脑/脊髓的T/B细胞及其对tlr2的需求的需求，以确定tlr2中的T/B细胞对脑/B细胞的需求。中枢神经系统及其相关的淋巴组织。该提议的创新是两个方面。首先，它提供了有关共生激活的galt和中枢神经系统炎症性脱髓鞘调节之间免疫相互作用的新信息，其次提出了一种新型的益生菌方法，作为对这种长期衰弱疾病的潜在治疗方法，对MS和其他自身免疫性条件的治疗产生了广泛的影响。