Establishment of disease mechanism of inflammatory and allergic disorders in the intestinal mucosa from the mucosal immune system and development for their treatments

本研究阐明了在胃肠道黏膜防御机制中起关键作用的粘膜免疫系统的结构基础、调控机制和发育过程，并建立了粘膜炎症性疾病和食物过敏的动物模型。这些研究为黏膜免疫系统领域的发展做出了重要贡献，为治疗和逆转胃肠黏膜免疫性炎症疾病提出了划时代的新思路：1)黏膜免疫系统的结构和功能，以及由于其调控失败而导致的炎症性和变应性肠病：(1)大量携带TcR-γδ的上皮内T细胞定位于肠粘膜的柱状上皮细胞之间，并被证明在细胞成熟和持续的免疫监测下维持了肠道的解剖前沿。CKit+LIN I…的小聚集体(2)激素和神经肽及其相关物质，如11β、HSD和Urocortin，对胃肠功能起着重要的调节作用，包括对水分和营养的吸收以及粘膜防御机制。(3)激活的巨噬细胞和淋巴细胞数量增加，中性粒细胞大量渗透，导致溃疡性结肠炎、克罗恩病和肠道过敏的黏膜损伤特征延长。2)食物过敏动物模型的建立和致敏机制的阐明：系统免疫的BALB/c小鼠和变应原特异性T细胞受体转基因小鼠在反复口服卵白蛋白后出现严重腹泻。3)预防和治疗食物过敏：(1)与胃酶消化的卵粘蛋白的IgE结合活性具有诊断价值和预测蛋清超敏反应。(2)食物过敏动物模型显示，每日核苷酸通过促进IL-12的产生而上调抗原特异性Th1免疫反应，并抑制抗原特异性IgE反应。这意味着，每日核苷酸可能有益于预防婴儿早期的变态反应性疾病。较少

The present investigation clarified the structural basis, regulatory mechanism and developmental process of the mucosal immune system, which play a crucial role in the mucosal defense mechanism in the gastrointestinal tract, and animal models for mucosal inflammatory diseases and food allergy were also established. These researches made a important contribution to the progress of the development in the field of the mucosal immune system, and proposed new and epoch-making ideas for treatment and prevertion of immuno-inflammatory disorders in the gastrointestinal mucosa.1) Structure and functions of the mucosal immune system, and inflammatory and allergic intestinal disorders induced by its regulatory failure :(1)Numerous intraepithelial T cells(IEL) bearing TCR- γδwere localized between columnar epithelial cells of the intestinal mucosa, and proved to maintain the anatomical front of the intestine under cellular maturation and constant immune surveillance. Small aggregates of ckit+Lin i … More mmature lymphocytes were precusors of IEL, named by cryptpatches.(2) Hormones and neuropeptides and their related substances such as 11β HSD and urocortin play important regulators for gastrointestinal functions including absorption of water and nutrients and mucosal defense mechanisms.(3) Increased number of activated macrophages and lymphocytes and abundant infiltration by neutrophils indued prolonged mucosal injuries characteristics for ulcerative colitis, Crohn's disease and intestinal allergy, respectively.2) Establishment of animal models for food allergy and elucidation of the mechanism for induction of allergy :Systemically primed BALB/c mice and allergen-specific T cell receptor transgenic mice developed severe diarrhea after repeated oral administration of ovoalbumin.3) Prevention and treatment of food alleregy :(1) IgE-binding activity, to pepsin-digested ovomucoid was of diagnostic value and prediction of the out growing of egg white hypersensitivity.(2) The animal model for food allergy showed that diatary nucleotides up-regulated the antigen-specific Th1 immune response through the enhancement of IL-12 production and suppressed the antigen specific IgE response. This implys that diatary nucleotides may be beneficial for the preventin for of allergic diseases in early infancy. Less