MECHANISMS OF AUTOIMMUNE DAMAGE OF INTESTINAL EPITHELIUM

肠上皮自身免疫损伤的机制

• 批准号: 6613848
• 负责人: Leo Lefrancois
• 金额: $ 21.94万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613848
• 关键词: CD4 molecule; CD8 molecule; T cell receptor; T lymphocyte; antigen presentation; autoantigens; autoimmune disorder; gastrointestinal epithelium; gene expression; genetically modified animals; laboratory mouse; ovalbumin; pathologic process

The recognition by the immune system of autoantigen expressed by intestinal epithelial cells (IEC) has yet to be studied. Moreover, how tolerance is maintained to intestine-specific antigens is unknown. A new model system will be utilized to address these issues. IEC-specific transgenic expression of a non-secreted form of ovalbumin as a model antigen has been accomplished. Preliminary results demonstrate that CD8 T cell recognition of this antigen results in immune destruction. The severity of disease is dependent on the amount of antigen expressed. In addition, tolerance induction to IEC autoantigen occurs apparently as a result of absorption of protein derived from IEC turnover. This model will allow us to determine the overall consequence of immune system recognition of intestine-specific antigen. The aims of this proposal are: Specific aim 1. To determine the mechanism of enterocyte damage by antigen-specific CD8 T cells. The molecular mechanisms of target organ damage will be defined. Specific Aim 2. To determine the consequence of CD8 and CD4 T cell reactivity in large intestinal epithelial cell antigen. The transgenic system will be modified to express antigen in large intestine epithelium and to provide inducible antigen expression. Specific aim 3. To determine the role of TCRgammadelta cells and keratinocyte growth factor in intestinal tissue repair. We will examine whether TCRgammadelta cells, which make up a large proportion of epithelial T cells and produce KGF, are involved in repair of damaged epithelium.

免疫系统对肠上皮细胞(IEC)表达的自身抗原的识别还有待研究。此外，如何维持对肠道特异性抗原的耐受性尚不清楚。将利用一个新的模式系统来解决这些问题。一种非分泌型卵清蛋白作为模型抗原的IEC特异性转基因表达已经完成。初步结果表明，CD8T细胞对该抗原的识别可导致免疫破坏。疾病的严重程度取决于所表达的抗原量。此外，对IEC自身抗原的耐受诱导明显是由于IEC周转所产生的蛋白质被吸收所致。这个模型将使我们能够确定免疫系统识别肠道特异性抗原的总体结果。本研究的目的是：1.明确抗原特异性CD8 T细胞对肠道细胞的损伤机制。将明确靶器官损伤的分子机制。具体目的2.确定大肠上皮细胞抗原CD8和CD4T细胞反应性的结果。转基因系统将被修改为在大肠上皮细胞中表达抗原，并提供可诱导的抗原表达。明确TCRGammadelta细胞和角质形成细胞生长因子在肠组织修复中的作用。我们将研究TCRGammadelta细胞是否参与受损上皮的修复。TCRGammadelta细胞占上皮T细胞的很大比例，并产生KGF。