Immunomodulatory role of lamina propria stromal cells

人类肠道炎症性疾病是由肠道中失调的适应性免疫应答介导的驱动过程。 公认的是，肠的基础免疫张力的特征在于通过免疫调节性（非辅助性T细胞1）T淋巴细胞产生细胞因子所表现的致耐受性应答。 尽管已认识到T辅助细胞亚群反应的二分法，并认识到非T辅助细胞1型反应在非炎症肠道中占优势，但尚不清楚为什么一种T辅助细胞亚群表型在肠道中占主导地位。 我们已经证明了环氧化酶-2（考克斯-2）依赖性花生四烯酸（AA）代谢产物在预防对饮食抗原的炎症反应中的作用。 在目前资助的K 08奖（DK-02608）的支持下，我们已经产生了数据，证明了固有层基质细胞亚群自发和连续产生（考克斯-2）依赖性代谢物。 这些观察结果支持了我们的假设，即固有层基质细胞在引导对管腔抗原的适应性免疫应答中发挥作用。 为了扩展在K 08奖下获得的观察结果，并更好地了解固有层基质细胞在对管腔抗原的免疫应答中的作用，我们提出了以下具体目标：1）开发和表征固有层基质细胞的克隆群体。2)评价固有层基质细胞影响辅助性T淋巴细胞反应的能力。这些特定目标的完成将涉及表征固有层基质细胞的克隆群体关于产生免疫相关分子，并鉴定这些固有层基质细胞在肠内的物理位置。 将分析固有层基质细胞的异质群体和固有层基质细胞的克隆群体影响抗原特异性T淋巴细胞应答的能力。 这些发现将允许识别具有影响肠道免疫反应能力的固有层基质细胞亚群，并将指导未来的研究检查肠道炎症动物模型中这些基质细胞优势的变化。

Human intestinal inflammatory diseases are driven processes mediated by a dysregulated adaptive immune response in the intestine. It is well accepted that the basal immunologic tone of the intestine is characterized by tolerogenic responses manifested by the production of cytokines by immunomodulatory (non-T helper 1) T-lymphocytes. Despite the recognized dictomy of T helper subset responses, and the recognition of the predominance of non-T helper 1responses in the uninflamed intestine, it is not understood why one T helper subset phenotype would predominate over another baseline in the intestine. We have demonstrated a role for cyclooxygenase- 2 (COX-2) dependent arachidonic acid (AA) metabolites produced by the small intestine lamina propria in prevention of an inflammatory response to dietary antigen. Under the auspices of the currently funded K08 award (DK-02608) we have generated data demonstrating spontaneous and continuous production of (COX-2) dependent metabolites by a subset of lamina propria stromal cells. These observations support our hypothesis that lamina propria stromal cells play a role in directing the adaptive immune response to luminal antigens. To expand upon the observations obtained under the K08 award and to gain a better understanding of the role of lamina propria stromal cells in the immune response to luminal antigens, we propose the following specific aims: 1) Develop and characterize clonal populations of lamina propria stromal cells. 2) Evaluate the ability of lamina propria stromal cells to influence helper T-lymphocyte responses. Completion of these specific aims will involve characterizing clonal populations of lamina propria stromal cells with respect to the production immunologically relevant molecules, and identifying the physical location of these lamina propria stromal cells within the intestine. Heterogeneous populations of lamina propria stromal cells and clonal populations of lamina propria stromal cells will be analyzed for their ability to influence antigen specific T-lymphocyte responses. These findings will allow identification of subsets of lamina propria stromal cells with the ability to influence immune response in the intestine, and will direct future studies examining changes in the predominance of these stromal cells in animal models of intestinal inflammation.