Lymphocyte Homing Mechanisms in Normal & Inflamed Colon

尽管在正常组织和炎症组织中的白细胞运输领域已经做了大量的工作 如皮肤和小肠，结肠是相对未被开发的。我们假设有选择性的 黏附分子表达的组合识别T细胞亚群，这些亚群优先归于 冒号。这一假说得到了以下发现的支持：淋巴细胞亚群通过其独特的 黏附分子的结合，表现出组织定位的差异性。此外，我们假设 黏附分子表达的改变在一定程度上解释了结肠过程中T细胞大量涌入的原因 发炎。基于这些假设，我的建议的具体目标是： 目的1.研究慢性自发性小鼠结肠炎模型角蛋白-8的炎症反应 (K8-/-)缺陷小鼠。在这个目标中，我们将描述与K8-/-相关的免疫反应 结肠炎。虽然K8是小肠和大肠中的一种主要角蛋白，但结肠是 K8-/-小鼠的炎症反应。我们发现K8结肠炎与Th2细胞因子的产生有关，Th2细胞因子是 易受抗生素治疗的。 目的2.比较T细胞和椎板内皮细胞中黏附和运输分子的表达 在正常和炎症条件下，结肠和小肠的固有膜，使用K8/和K8-/- 老鼠。在这里，我们将使用流式细胞术和免疫组织化学来确定不同的黏附和 结肠内皮细胞和T细胞的运输分子表达与其他组织的比较 小肠。 目的3.确定目标2中确定的分子是否介导结肠固有层的重新启动 正常和炎症结肠中的活体淋巴细胞。在这里，我们将研究各种粘连的作用 分子，通过实施采用细胞转移和在短期归巢分析中使用封闭抗体。 K8-/-小鼠是炎症性肠病(IBD)的一种独特模型，因为它代表了一种主要的 上皮细胞缺陷，为研究炎症和归巢到结肠提供大量细胞。 这项拟议的研究应该会提高我们对免疫细胞向结肠运输的理解，为我们提供见解 探讨IBD可能的致病机制，并有可能为IBD开辟新的治疗靶点。

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.