MECHANISMS OF AUTOIMMUNE DAMAGE OF INTESTINAL EPITHELIUM

肠上皮自身免疫损伤的机制

• 批准号: 6178418
• 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/6178418
• 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，如何维持耐受性，以马槟榔特异性抗原是未知的。将利用新的模型系统来解决这些问题。已经完成了作为模型抗原的非分泌形式的卵清蛋白的IEC特异性转基因表达。初步结果表明，这种抗原的CD8 T细胞识别导致免疫破坏。疾病的严重程度取决于抗原表达的量。此外，对IEC自身抗原的耐受性诱导显然是由于吸收IEC周转产生的蛋白质而发生的。该模型将使我们能够确定免疫系统识别精氨酸特异性抗原的总体结果。该提案的目标是：具体目标1。确定抗原特异性CD8 T细胞损伤肠上皮细胞的机制。将定义靶器官损伤的分子机制。具体目标2。目的探讨大肠上皮细胞抗原中CD8和CD4 T细胞反应性的影响。将对转基因系统进行修饰以在大肠上皮中表达抗原并提供诱导型抗原表达。具体目标3。确定TCR γ δ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TCR γ δ细胞是否参与受损上皮的修复，TCR γ δ细胞在上皮T细胞中占很大比例并产生KGF。