CHARACTERIZATION OF GLUTEN-SENSISTIVE RHESUS MACAQUES

麸质敏感恒河猴的特征

• 批准号: 8172968
• 负责人: KAROL SESTAK
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172968
• 关键词: Animals; Antibodies; Antibody-Producing Cells; Architecture; Biopsy; Brush Border; Celiac Disease; Childhood; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Diarrhea; Diet; Disease remission; Distal; Duodenum; Endoscopes; Epithelial; Epithelium; Exhibits; Funding; Gliadin; Gluten; Grant; Histopathology; Human; Immunoglobulin A; Immunoglobulin G; Infiltration; Institution; Intestines; Label; Lamina Propria; Lymphocyte; Macaca; Macaca mulatta; Microscopic; Modeling; Peptides; Permeability; Plasma; Proteins; Recording of previous events; Research; Research Personnel; Resistance; Resources; Serological; Source; Study models; Tissues; United States National Institutes of Health; Villous; Villous Atrophy; base; in vivo; transglutaminase 2; villin

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Based on clinical, histopathological and serological similarities to human celiac disease, we recently established the rhesus macaque model of gluten sensitivity. In this study, we further characterized this condition based on presence of anti-tissue transglutaminase 2 (TG2) antibodies, increased intestinal permeability and transepithelial transport of a proteolytically resistant, immunotoxic, 33-residue peptide from alpha-2-gliadin in the distal duodenum of gluten-sensitive macaques. Six rhesus macaques were selected for study from a pool of 500, including two healthy controls and four gluten-sensitive animals with elevated anti-gliadin or anti-TG2 antibodies as well as history of non-infectious chronic diarrhea. Pediatric endoscope-guided pinch biopsies were collected from each animal's distal duodenum following administration of a gluten-containing diet (GD) and again after remission by gluten-free diet (GFD). Control biopsies always showed normal villous architecture, whereas gluten-sensitive animals on GD exhibited histopathology ranging from mild lymphocytic infiltration to villous atrophy, typical of human CD. Immunofluorescent microscopic analysis of biopsies revealed IgG+ and IgA+ plasma-like cells producing antibodies that colocalized with TG2 in gluten-sensitive macaques only. Following instillation in vivo, the Cy-3-labeled 33-residue gluten peptide colocalized with the brush border protein villin in all animals. In a substantially enteropathic macaque with "leaky" duodenum, the peptide penetrated beneath the epithelium into the lamina propria. The rhesus macaque model of gluten sensitivity not only resembles the histopathology of CD but it also may provide a model for studying intestinal permeability in states of epithelial integrity and disrepair.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 基于与人乳糜泻的临床，组织病理学和血清学相似性，我们最近建立了麸杆猕猴模型的麸质敏感性。在这项研究中，我们进一步表征了这种条件，基于抗组织转基谷氨酰胺酶2（TG2）抗体的存在，增加的肠道渗透性和增加的蛋白水解抗性，免疫毒性，33个蛋白质毒性，33个抗alpha-2-胶质素的33个替代肽的蛋白质毒性。从500池中选择了六个恒河猕猴进行研究，其中包括两种健康对照和四只对抗胶质素或抗TG2抗体升高的对麸质敏感动物以及非感染性慢性腹泻病史。服用含麸质的饮食（GD）后，从每只动物的远端十二指肠收集了儿科内窥镜引导的捏动物，并在无麸质饮食（GFD）缓解后再次收集。对照活检始终显示出正常的绒毛结构，而GD上对麸质敏感的动物表现出从轻度淋巴细胞浸润到绒毛萎缩的组织病理学，典型的人类CD。活检的免疫荧光显微镜分析显示，IgG+和IgA+等离子体样细胞产生与麸质敏感猕猴一起与TG2共定位的抗体。在体内滴注后，Cy-3标记的33个残留的麸质肽与所有动物的刷子边界蛋白绒毛共定位。在基本上带有“漏水”十二指肠的肠道猕猴中，肽在上皮下方渗透到固有层中。麸质敏感性的恒河猕猴模型不仅类似于CD的组织病理学，而且还可以为研究上皮完整性和失修状态的肠道通透性提供模型。