Targeting L-Selectin in Chronic Murine Ileitis

描述(申请人提供)：临床研究支持黏附分子阻滞剂(即Natalizumab)治疗克罗恩病(CD)的疗效，但导致靶向特定黏附分子(即整合素14)的临床前数据来自对结肠炎动物模型的研究。然而，60%的CD患者患有回肠炎。我们在新的小鼠回肠炎模型(即SAMP1/Yit，肿瘤坏死因子？ARE)中的工作支持了新的概念，即运输到末端回肠利用一组重叠但不同的分子，部分不同于那些调节运输到结肠的分子。在我们的模型中，在删除了对生理运输或归巢到结肠至关重要的分子(即CCR9、整合素1427或1E27)后，回肠炎的减弱就说明了这一点。出乎意料的是，缺乏L选择素或负责其功能配体的相应硫酸盐转移酶的小鼠患上的疾病大大减轻。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。肿瘤坏死因子？ARE模型代表了一种独特的工具，可以用来确定L-选择素缺乏所介导的疾病减弱的机制。为了进一步探讨这一假说，我们提出了三个具体目标。1.剖析L-选择素缺乏在回肠炎发病中的免疫作用。2.评价血管内皮细胞配体在L-选择素缺乏介导的回肠炎中的作用。3.研究L-选择素缺陷型肿瘤坏死因子受体拮抗回肠炎的造血学决定因素。总体而言，这些研究有可能为T细胞如何到达小肠、诱发和维持回肠炎开辟新的视角。考虑到肿瘤坏死因子a区模型和CD之间的相似性，我们的发现可能会导致新的治疗靶点。与公共健康相关：白血球通常从血液流向肠道，在那里它们巡视外部入侵者。然而，在克罗恩病(CD)中，这种交通是过度的，导致肠道损伤，并经常出现丧失工作能力的症状。最近的研究表明，减少过度的白血球运输的药物，如Natalizumab，对治疗克罗恩病有效。但在极少数情况下，会出现严重的并发症，因为我们并不完全了解Natalizumab是如何起作用的。我们一直在研究一种小鼠品系，它会患上一种类似于CD的慢性小肠炎性疾病，并注意到当这些小鼠缺乏L选择素时，它们的疾病实际上是不存在的。在这些研究中，我们将试图了解不使用L-选择素是如何保护这些小鼠免受IBD的影响。了解白细胞是如何利用这些分子进入肠道的，可能会让我们减少白细胞的运输，以有效和安全的方式治疗CD。

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.