CHARACTERIZATION OF GLUTEN-SENSISTIVE RHESUS MACAQUES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 基于临床、组织病理学和血清学与人类乳糜泻的相似性，我们最近建立了谷蛋白敏感性的恒河猴模型。在这项研究中，我们进一步表征了这种情况的基础上存在的抗组织转氨酶2（TG 2）抗体，增加肠道通透性和跨上皮转运的蛋白水解抗性，免疫毒性，33个残基的肽从α-2-麦醇溶蛋白在十二指肠远端的面筋敏感猕猴。从500只猕猴中选择6只猕猴进行研究，包括2只健康对照和4只抗麦醇溶蛋白或抗TG 2抗体升高以及有非感染性慢性腹泻史的谷蛋白敏感动物。在给予含麸质饮食（GD）后和通过无麸质饮食（GFD）缓解后再次从每只动物的远端十二指肠收集儿科内窥镜引导的捏夹活检。对照组活组织检查始终显示正常的绒毛结构，而GD的谷蛋白敏感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变化，这是人类CD的典型特征。活检的免疫荧光显微镜分析显示IgG+和伊加+血浆样细胞产生的抗体，与TG 2共定位在面筋敏感的猕猴。在体内滴注后，Cy-3标记的33个残基的谷蛋白肽与所有动物的刷状缘蛋白绒毛共定位。在具有“渗漏”十二指肠的基本上肠病性猕猴中，肽穿透上皮下方进入固有层。麸质敏感性的恒河猴模型不仅类似于CD的组织病理学，而且还可以提供用于研究上皮完整性和破损状态下的肠通透性的模型。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.