GALT mediated protection against CNS demyelination: Role of commensal bacteria

描述（由申请方提供）：最近的研究揭示了肠道相关淋巴组织（GALT）及其与肠道细菌种群在外周免疫平衡中的相互作用的重要性。我们已经证明，改变肠道细菌种群可以防止EAE，人类多发性硬化症的实验模型。预防性和治疗性口服给予高度纯化的、结构表征的细菌抗原制剂，即来源于人口腔脆弱拟杆菌的多糖A（PSA），可以在IL-10依赖性机制中保护免受EAE。值得注意的是，当与未处理的对照相比时，在受保护小鼠的CLN中，CD 103 + CD 11 C高GALT衍生的DC和FoxP 3 +Treg细胞均显著增加，同时IL-17下调。我们假设特异性肠道菌抗原，特别是人肠道菌B的荚膜多糖A（PSA）。fragilis，当口服给药时，可以防止CNS脱髓鞘疾病。通过粘膜DC或B细胞群的TLR-2连接介导保护，所述粘膜DC或B细胞群被极化并迁移到CNS和相关淋巴组织，在那里它们诱导控制炎症和脱髓鞘的疾病修饰调节性T细胞。具体目标是：1）鉴定EAE小鼠中与PSA免疫相关的APC并使其表型化，2）鉴定参与PSA相关APC以及T/B细胞向脑/脊髓和CNS相关淋巴组织的迁移和运输的特异性分子，和3）确定CNS及其相关淋巴组织中PSA诱导CD 39 +/-T细胞和B细胞中TLR 2的需要。这项建议的创新之处有两个方面。首先，它提供了新的信息之间的免疫相互作用的唾液酸激活的GALT和调节中枢神经系统炎性脱髓鞘和第二提出了一种新的益生菌的方法作为一种潜在的治疗对这种慢性衰弱性疾病的治疗MS和其他自身免疫性疾病的广泛影响。

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.