Targeting L-Selectin in Chronic Murine Ileitis

描述（由申请人提供）：临床研究支持粘附分子阻断（即Natalizumab）对克罗恩病（CD）的治疗效果，但导致特异性粘附分子（即整合素14）靶向的临床前数据来自结肠炎动物模型的研究。然而，60%的乳糜泻患者患有回肠炎。我们在新型小鼠回肠炎模型(即SAMP1/Yit， TNF？ARE)支持一个新概念，即到回肠末端的运输利用一组重叠但不同的分子，部分不同于那些介导到结肠的运输。在我们的模型中，删除对生理运输或归归结肠至关重要的分子（即CCR9、整合素1427或1E27）后，回肠炎的衰减不足就说明了这一点。出人意料地,肿瘤坏死因子?缺乏l -选择素或相应的负责其功能配体的硫转移酶的ARE小鼠，会发展为严重减毒的疾病。因此，我们的中心假设是l -选择素在小鼠回肠炎的发病机制中起关键作用。TNF ？ARE模型是一种独特的工具，可以识别由l -选择素缺乏介导的疾病衰减机制。我们提出了三个具体目标来进一步探索这一假设。1. 探讨l -选择素缺乏对回肠炎的免疫作用。2. 评估内皮配体在l -选择素缺乏介导的回肠炎衰减中的作用。3. 研究L-选择素缺乏的TNF中回肠炎衰减的造血决定因素？是老鼠。总的来说，这些研究有可能为T细胞如何到达小肠，诱导和维持回肠炎开辟新的视角。鉴于TNF a ARE模型和CD之间的相似性，我们的发现可能会导致新的治疗靶点。公共卫生相关性：白细胞通常从血流进入肠道，在那里它们巡逻外部入侵者。然而，在克罗恩病（CD）中，这种交通过多，导致肠道损伤和经常丧失能力的症状。最近的研究表明，减少过多白细胞流量的药物，如Natalizumab，对治疗克罗恩病有效。然而，在极少数情况下会出现严重的并发症，因为我们不完全了解Natalizumab是如何起作用的。我们一直在研究一种患有小肠慢性炎症性疾病（类似于乳糜泻）的小鼠菌株，并注意到当这些小鼠缺乏l -选择素（一种参与白细胞进入肠道的分子）时，它们的疾病实际上是不存在的。在这些研究中，我们将试图了解在没有l -选择素的情况下，这些小鼠如何免受IBD的影响。了解白细胞如何利用这些分子进入肠道可以让我们减少白细胞的运输以有效和安全的方式治疗乳糜泻。

DESCRIPTION (provided by applicant): Clinical studies support the therapeutic efficacy of adhesion molecule blockade (i.e. Natalizumab) in Crohn's disease (CD), yet the preclinical data that led to the targeting of specific adhesion molecules (i.e. integrin 14) originated from studies in animal models of colitis. However, sixty percent of patients with CD suffer from ileitis. Our work in novel murine models of ileitis (i.e. SAMP1/Yit, TNF?ARE) supports the novel concept that trafficking to the terminal ileum utilizes an overlapping yet distinct set of molecules, in part different from those that mediate traffic to the colon. This is illustrated by the lack of attenuation of ileitis seen after deletion of molecules critical for physiological trafficking or homing into the colon (i.e. CCR9, integrins 1427 or 1E27) in our model. Unexpectedly, TNF?ARE mice that lack L-selectin or the corresponding sulfotransferases responsible for its functional ligands, develop greatly attenuated disease. Thus our central hypothesis is that L-selectin is critically involved in the pathogenesis of murine ileitis. The TNF ?ARE model represents a unique tool to identify the mechanisms that underlie the attenuation of disease, mediated by L-selectin deficiency. We propose three specific aims to further explore this hypothesis. 1. Dissect the immunological effects of L-selectin deficiency in ileitis. 2. Assess the role of endothelial ligands on the attenuation of ileitis mediated by L-selectin deficiency. 3. Investigate hematopoietic determinants underlying attenuation of ileitis in L- selectin-deficient TNF ?ARE mice. Overall, these studies have the potential to open new perspectives on how T cells reach the small intestine, to induce and maintain ileitis. Given the similarities between the TNF a ARE model and CD, our findings may potentially lead to new therapeutic targets. PUBLIC HEALTH RELEVANCE: White blood cells normally traffic from the blood stream into the intestine, where they patrol for outside invaders. However in Crohn's disease (CD) this traffic is excessive, leading to intestinal damage and often incapacitating symptoms. Recent studies have shown that drugs that reduce excessive white blood cell traffic, like Natalizumab, are effective to treat Crohn's. Yet in rare occasions there are serious complications, as we do not fully understand how Natalizumab works. We have been studying a mouse strain that develops a chronic inflammatory disease of the small intestine, similar to CD and have noticed that when these mice lack L-selectin, a molecule that is involved in the traffic of white cells into the intestine, their disease is virtually absent. In these studies we will attempt to understand how by not having L-selectin these mice are protected from developing IBD. Understanding how white cells use these molecules to travel to the intestine may allow us to reduce white cell traffic and treat CD in an effective and safe manner.