CHARACTERIZATION OF GLUTEN-SENSISTIVE RHESUS MACAQUES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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，我们最近建立了恒河猴的面筋敏感性模型。在这项研究中，我们基于抗组织转谷氨酰胺酶2(TG2)抗体的存在，增加了肠道通透性，以及面筋敏感猕猴十二指肠远端α-2-醇溶蛋白33个残基的蛋白水解性、免疫毒性、33个残基的跨皮转运，进一步表征了这种情况。从500只猕猴中挑选了6只进行研究，其中包括2只健康对照和4只面筋敏感动物，这些动物的抗醇溶蛋白或抗TG2抗体升高，并有非传染性慢性腹泻病史。每只动物在内窥镜引导下，在给予含面筋饮食(GD)和无面筋饮食(GFD)缓解后，从每只动物的十二指肠末端收集夹击活检组织。对照活检总是显示正常的绒毛结构，而面筋敏感的动物在GD上表现出从轻微的淋巴细胞渗透到绒毛萎缩的组织病理学，这是典型的人类CD。免疫荧光显微镜对活检组织的分析显示，仅在面筋敏感的猕猴中，免疫球蛋白+和免疫球蛋白A+浆样细胞产生与TG2共同定位的抗体。体内滴注后，Cy-3标记的33个残基的谷蛋白多肽与刷状边界蛋白Villin在所有动物中共定位。在一只患有十二指肠“漏”的严重肠病猕猴中，多肽穿透上皮下进入固有层。恒河猴的谷蛋白敏感性模型不仅与CD的组织病理学相似，而且可能为研究肠道上皮完整和破损状态下的通透性提供一个模型。

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.