Targeting L-Selectin in Chronic Murine Ileitis

描述（由申请方提供）：临床研究支持粘附分子阻断剂（即那他珠单抗）在克罗恩病（CD）中的治疗疗效，但导致靶向特定粘附分子（即整联蛋白14）的临床前数据来自结肠炎动物模型研究。然而，60%的CD患者患有回肠炎。我们在新型小鼠回肠炎模型（即SAMP 1/Yit，TNF？ARE）支持新的概念，即运输到末端回肠利用重叠但不同的分子组，部分不同于介导运输到结肠的那些分子。这通过在我们的模型中缺失对于生理运输或归巢到结肠中至关重要的分子（即CCR 9、整合素1427或1 E27）后观察到的回肠炎缺乏衰减来说明。然而，TNF？缺乏L-选择素或负责其功能性配体的相应磺基转移酶的ARE小鼠发展出大大减弱的疾病。因此，我们的中心假设是，L-选择素是至关重要的参与小鼠回肠炎的发病机制。TNF？ARE模型代表了一种独特的工具，以确定疾病的衰减，介导的L-选择素缺乏的机制。我们提出了三个具体目标，以进一步探讨这一假设。1.探讨L-选择素缺乏对回肠炎的免疫学影响。2.评估内皮配体在减轻L-选择素缺乏介导的回肠炎中的作用。3.探讨L-选择素缺陷型TNF？回肠炎减毒的造血决定因素？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 α 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：白色血细胞通常从血流中进入肠道，在那里它们巡逻以抵御外部入侵者。然而，在克罗恩病（CD）中，这种运输是过度的，导致肠道损伤和经常失能的症状。最近的研究表明，减少过多的白色血细胞运输的药物，如那他珠单抗，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那他珠单抗的作用机制。我们一直在研究一种小鼠品系，这种小鼠会患上一种类似CD的慢性小肠炎性疾病，我们注意到，当这些小鼠缺乏L-选择素（一种参与白色细胞进入肠道的分子）时，它们的疾病几乎不存在。在这些研究中，我们将试图了解没有L-选择素如何保护这些小鼠免受IBD的发展。了解白色细胞如何利用这些分子前往肠道，可能使我们能够减少白色细胞的运输，并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.