T cell homing in intestinal graft-versus-host disease

描述(由申请人提供)：移植物抗宿主病(GVHD)仍然是异基因造血干细胞移植(HSCT)受者移植后发病率和死亡率的主要原因。肠道不仅是GVHD的主要靶器官，也是内毒素和炎性细胞因子的来源，这些细胞因子可以放大GVHD在肠道和其他地方的发展。AII反应性供者T细胞在异基因HSCT后GVHD和移植物抗肿瘤(GVT)活动中起着关键作用。T细胞转运在T细胞免疫应答和T细胞介导性疾病中起着重要作用，主要受整合素和趋化因子的调节。该建议的中心假设是：(1)整合素和趋化因子配体及受体是T细胞转运到正常或炎症肠道所必需的，在急性肠道GVHD的发生和发展中起重要作用，(2)抑制这些整合素和趋化因子可以缓解急性肠道和全身性GVHD的发展，同时阻止所有其他组织中同种异体反应性T细胞的GVT活性。基于初步数据，包括肠道GVHD期间基因表达的动力学分析(使用DNA微阵列)，选择了以下蛋白质用于同种异体HSCT小鼠模型的进一步研究：α-4/β-7整合素，趋化因子受体CCR2和CCR9，以及趋化因子CCL25。为了研究抑制这些分子对肠道和全身GVHD和GVT活性的影响，将使用缺乏β-7、CCR2和CCR9、α-4/β-7、β-7和CCL25中和抗体的小鼠。随后，将通过非侵入性成像技术(生物发光成像、PET和CT扫描)结合使用基因标记的供体T细胞的免疫荧光显微镜来评估这些抑制策略的效果。这些研究将有助于更好地从机制上了解肠道GVHD，并为治疗或预防肠道GVHD的新策略提供临床前数据，同时减少GVT的活动。

DESCRIPTION (provided by applicant): Graft-versus-host-disease (GVHD) remains a major cause of post-transplant morbidity and mortality in recipients of an allogeneic hematopoietic stem cell transplantation (HSCT). The gut is not only a primary GVHD target organ, but is also the source of endotoxin and inflammatory cytokines, which can amplify the development of GVHD in the intestines and elsewhere. AIIoreactive donor T cells play a pivotal role in GVHD and graft-versus-tumor (GVT) activity after an allogeneic HSCT. T cell trafficking has an important role in the T cell immune response and T cell mediated diseases, and is mostly regulated by integrins and chemokines. The central hypotheses of this proposal are that: (1) integrins and chemokine ligands and receptors, which are required for T cell trafficking to the normal or inflamed intestines, are important in the development of acute intestinal GVHD, and (2) inhibition of these integrins and chemokines can ameliorate the development of acute intestinal and systemic GVHD while sparing GVT activity by alloreactive T cells in all other tissues. Based upon preliminary data including a kinetic analysis of gene expression (using DNA micro-arrays) during intestinal GVHD, the following proteins were selected for further study in mouse models for allogeneic HSCT: the alpha-4/beta-7 integrin, the chemokine receptors CCR2 and CCR9, and the chemokine CCL25. To study the effects of inhibition of these molecules on the development of intestinal and systemic GVHD and GVT activity, mice deficient for beta-7, CCR2 and CCR9, neutralizing antibodies for alpha-4/beta-7, beta-7 and CCL25 will be used. Subsequently, the effects of these inhibitory strategies will be assessed by non-invasive imaging techniques (bioluminescence imaging, PET and CT scanning) in combination with immunofluorescence microscopy using genetically labeled donor T cells. These studies will contribute to a better mechanistic understanding of intestinal GVHD and provide preclinical data for new strategies to treat or prevent intestinal GVHD, while sparing GVT activity.