Immunomodulatory role of lamina propria stromal cells

人类肠道炎症性疾病是由肠道内失调的适应性免疫反应所介导的过程。众所周知，肠道的基础免疫张力以免疫调节(非辅助性T细胞1)T淋巴细胞产生细胞因子所表现的耐受性反应为特征。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辅助细胞亚群反应在非炎症肠道中的优势，但尚不清楚为什么一种T辅助细胞亚群表型会在肠道中主导另一种基线。我们已经证明了环氧合酶-2(COX-2)依赖的花生四烯酸(AA)代谢产物在防止对饮食抗原的炎症反应中的作用。在目前资助的K08奖(DK-02608)的支持下，我们产生了显示固有层基质细胞子集自发地和连续地产生(COX-2)依赖的代谢物的数据。这些观察结果支持我们的假设，即固有层基质细胞在引导对管腔抗原的适应性免疫反应中发挥作用。为了更好地理解固有层基质细胞在管腔抗原免疫反应中的作用，我们提出了以下具体目标：1)培养和鉴定固有层基质细胞克隆群体。2)评估固有层基质细胞影响辅助性T淋巴细胞反应的能力。完成这些特定的目标将涉及确定固有层基质细胞的克隆群体与产生免疫相关分子的特征，并确定这些固有层基质细胞在肠道中的物理位置。不同群体的固有层基质细胞和克隆的固有层基质细胞群体将被分析其影响抗原特异性T淋巴细胞反应的能力。这些发现将有助于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，检查这些基质细胞在肠道炎症动物模型中优势地位的变化。

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.