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，而且也是内毒素和炎性细胞因子的来源，其可以放大肠道和其他地方的GVHD的发展。全反应性供者T细胞在异基因造血干细胞移植后GVHD和移植物抗肿瘤（GVT）活性中起关键作用。T细胞运输在T细胞免疫应答和T细胞介导的疾病中具有重要作用，并且主要由整合素和趋化因子调节。该提议的中心假设是：（1）T细胞运输到正常或发炎的肠所需的整联蛋白和趋化因子配体和受体在急性肠GVHD的发展中是重要的，和（2）这些整联蛋白和趋化因子的抑制可以改善急性肠和全身GVHD的发展，同时保留所有其他组织中同种异体反应性T细胞的GVT活性。基于包括肠道GVHD期间基因表达的动力学分析（使用DNA微阵列）的初步数据，选择以下蛋白质用于在同种异体HSCT的小鼠模型中进一步研究：α-4/β-7整联蛋白、趋化因子受体CCR 2和CCR 9以及趋化因子CCL 25。为了研究这些分子的抑制对肠和全身GVHD和GVT活性的发展的影响，将使用β-7、CCR 2和CCR 9缺陷的小鼠、α-4/β-7、β-7和CCL 25的中和抗体。随后，这些抑制策略的效果将通过非侵入性成像技术（生物发光成像，PET和CT扫描）结合免疫荧光显微镜使用遗传标记的供体T细胞进行评估。这些研究将有助于更好地了解肠道GVHD的机制，并为治疗或预防肠道GVHD的新策略提供临床前数据，同时保留GVT活性。

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.