Role of STAT1 and STAT3 in Graft versus Host Disease and Graft versus Leukemia Ef

描述（由申请人提供）：由于相关的移植物抗白血病（GVL）效应，同种异体血液或骨髓移植（BMT）是一种高度有效且可能治愈许多造血系统恶性肿瘤的治疗方法。然而，这种有益的GVL效应经常被移植物抗宿主病（GVHD）的发展所抵消。GVHD的发展严重依赖于GVHD靶器官中的全身和局部炎症反应。我们假设GVHD靶器官中早期炎症信号通路的激活控制供体T细胞向GVHD靶器官的募集（例如粘附分子、趋化因子的上调）和组织损伤的诱导。因此，识别信号通路和候选分子可能会导致未来的靶向治疗和预防GVHD的新方法。Janus激酶（JAK）-信号转录激活因子（STAT）途径是将细胞因子信号转化为调节促炎和抗炎反应的基因表达程序的主要信号传导途径。使用同种异体BMT的啮齿动物模型，我们已经确定了STAT 1和STAT 3的激活是GVHD靶器官中GVHD诱导过程中的早期事件。我们认为STAT 1和STAT 3是GVHD靶器官炎症反应所必需的介质，相反，STAT 1和STAT 3可能拮抗GVL效应。因此，本提案的主要目标是测试STAT 1和STAT 3在GVHD和GVL中的作用。在目的1中，我们将使用组成性STAT 1或条件性STAT 3基因缺陷小鼠和STAT 1和STAT 3的小分子抑制剂来研究STAT 1和STAT 3作为GVHD添加的介导物的需求。在不同的免疫遗传学宿主-供体差异中以及在未调节的小鼠中，致死照射后将诱导GVHD。此外，使用STAT 1或STAT 3基因缺陷小鼠，我们将剖析宿主与供体STAT 1/3对GVHD发展的需求。在目的2中，我们将研究STAT 1和STAT 3在调节淋巴造血细胞GVH反应和GVL效应中的作用，在条件诱导的炎症的存在或不存在的情况下，并将解决的问题是否STAT 1或STAT 3的操作可能会增加GVL效应。 公共卫生相关性：异基因造血干细胞移植是治疗造血系统的一些恶性和良性疾病的选择。移植物抗宿主病（GVHD）及其并发症仍然是异基因造血干细胞移植后发病和死亡的主要原因。15%至50%的患者将死于GVHD或感染性并发症，并排除了这种潜在的治愈性治疗选择的广泛应用。因此，开发新的方法具有重要意义，其允许维持移植物抗白血病（GVL）反应，但减少或预防GVHD。

DESCRIPTION (provided by applicant): Allogeneic blood or marrow transplantation (BMT) is a highly effective and potentially curative treatment for a number of hematopoietic malignancies due to the associated Graft versus Leukemia (GVL) effect. However, this beneficial GVL effect is frequently offset by the development of Graft versus Host Disease (GVHD). Development of GVHD is critically dependent on a systemic and local inflammatory response in GVHD target organs. We hypothesize that activation of early inflammatory signaling pathways in GVHD target organs controls recruitment of donor T cells to GVHD target organs (e.g. upregulation of adhesion molecules, chemokines) and induction of tissue damage. Therefore, identification of signaling pathways and candidate molecules may lead to novel approaches for future targeted therapy and prevention of GVHD. The Janus Kinase (JAK) - Signal activator of transcription (STAT) pathway is a major signaling pathway converting cytokine signals into gene expression programs regulating pro- and anti-inflammatory responses. Using rodent models of allogeneic BMT we have identified the activation of STAT1 and STAT3 to be an early event during the induction of GVHD in GVHD target organs. We propose that STAT1 and STAT3 are required mediators of inflammation in GVHD target organs and that conversely STAT1 and STAT3 may antagonize GVL effects. It is therefore the primary goal of this proposal to test the role of STAT1 and STAT3 in GVHD and GVL. In Aim 1 we will study the requirement of STAT1 and STAT3 as mediators for GVHD addition using constitutive STAT1 or conditional STAT3 gene deficient mice and small molecule inhibitors of STAT1 and STAT3. GVHD will be induced following lethal irradiation in different immunogenetic host-donor disparities as well as in unconditioned mice. In addition using STAT1 or STAT3 gene deficient mice we will dissect the requirement of host versus donor STAT1/3 for the development of GVHD. In Aim 2 we will study the role of STAT1 and STAT3 in regulating lymphohematopoietic GVH reactions and GVL effects in the absence or presence of conditioning-induced inflammation and will address the question whether manipulation of STAT1 or STAT3 might augment GVL effect. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is the treatment of choice for a number of malignant and benign diseases of the hematopoietic system. Graft versus Host Disease (GVHD) and its complications are still the leading causes of morbidity and mortality after allogeneic stem cell transplantation. 15% to 50% of patients will die due to GVHD or infectious complications and precluding the widespread application of this potential curative treatment option. Therefore, it is of high significance to develop novel approaches, which allow to maintain Graft versus Leukemia (GVL) reactions, but diminish or prevent GVHD.