Lymphocyte Homing Mechanisms in Normal & Inflamed Colon

尽管在正常和炎症组织中白细胞运输领域已经做了大量的工作， 例如皮肤和小肠，结肠相对未被探索。我们假设选择性的 粘附分子表达的组合鉴定了优先归巢于粘附分子的T细胞亚群。 结肠这一假说得到了以下发现的支持，即淋巴细胞亚群通过其独特的 粘附分子的组合，表现出差异性组织定位。此外，我们假设， 粘附分子表达的改变，部分解释了结肠炎期间T细胞的大量涌入， 炎症基于这些假设，我的建议的具体目标是： 目标1。表征慢性自发性小鼠结肠炎模型中的炎症，角蛋白-8 K8 -/-小鼠。在这个目标中，我们将表征与K8 -/- 结肠炎虽然K8是小肠和大肠中的主要角蛋白，但结肠是K8的主要靶点。 K8 -/-小鼠的炎症。我们发现K8 -/-结肠炎与Th 2细胞因子的产生有关， 适合抗生素治疗。 目标2.比较板层内T细胞和内皮细胞中粘附和运输分子的表达 结肠和小肠固有，在正常和炎症条件下，使用K8 +/+和K8 -/- 小鼠在这里，我们将使用流式细胞术和免疫组织化学来确定差异粘附和 与其他组织相比，结肠内皮细胞和T细胞的运输分子表达，包括 小肠。 目标3：确定在aim 2中鉴定的分子是否介导结肠固有层的募集 淋巴细胞在体内正常和发炎的结肠。在这里，我们将研究各种粘合剂的作用， 通过进行过继细胞转移和在短期归巢测定中使用阻断抗体， K8 -/-小鼠是炎症性肠病（IBD）的独特模型，因为它代表了原发性炎症性肠病（IBD）。 上皮细胞缺陷，并提供了大量的细胞来研究炎症和归巢到结肠。 这项拟议中的研究应该提高我们对免疫细胞运输到结肠的理解， 研究IBD可能的致病机制，并可能为IBD提供新的治疗靶点。

Although extensive work has been done in the area of leukocyte trafficking in normal and inflamed tissues such as the skin and small intestine, the colon is relatively unexplored. We hypothesize that selective combinations of adhesion molecule expression identifies subsets of T cells that preferentially home to the colon. This hypothesis is supported by findings that subsets of lymphocytes, via their expression of unique combination of adhesion molecules, manifest differential tissue localization. Furthermore, we postulate that altered adhesion molecule expression, in part, explains the massive influx of T cells seen during colonic inflammation. Based on these hypotheses, the specific aims of my proposal are: Aim 1. Characterize the inflammation in a chronic spontaneous mouse colitis model, the keratin-8 deficient (K8 -/-) mice. In this aim we will characterize the immune response associated with the K8 -/- colitis. Although K8 is a major keratin in the small and large intestine, the colon is the primary target of inflammation in K8 -/- mice. We find that K8 -/- colitis is associated with Th2 cytokine production which is amenable to antibiotic treatment. Aim 2. Compare adhesion and trafficking molecule expression in T and endothelial cells within lamina propria of the colon and small intestine, under normal and inflammatory conditions, using K8 +/+ and K8 -/- mice. Here we will use flow cytometry and immunohistochemistry to determine differential adhesion and trafficking molecule expression by colon endothelial and T cells as compared with other tissues, including the small intestine. Aim 3. Determine whether molecules identified in aim 2 mediate recruitment of colon lamina propria lymphocytes in vivo in normal and inflamed colons. Here we will study the role of various adhesion molecules, by perfoming adoptive cell transfers and using blocking antibodies in short-term homing assays. The K8 -/- mouse is a unique model of inflammatory bowel disease (IBD) in that it represents a primary epithelial cell defect, and provides significant cell number to study inflammation and homing to the colon. The proposed study should improve our understanding of immune cell trafficking to the colon, offer insights into possible IBD pathogenic mechanisms, and potentially unfold new therapeutic targets to consider for IBD.