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。

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.