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

STAT1 和 STAT3 在移植物抗宿主病和移植物抗白血病 Ef 中的作用

• 批准号: 7922151
• 负责人: Markus Y. Mapara
• 金额: $ 37.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-19 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922151
• 关键词: Address; Alloantigen; Allogenic; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Behavior Therapy; Benign; Bioluminescence; Blood; Bone Marrow Transplantation; Cell Adhesion Molecules; Cell Death; Cell Survival; Cytokine Signaling; Development; Disease; Donor Lymphocyte Infusion; Down-Regulation; Event; Future; Gene Expression; Goals; Growth; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Histone Deacetylase Inhibitor; Image; Immunogenetics; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Janus kinase; Lead; Lipopolysaccharides; Luciferases; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediation; Mediator of activation protein; Molecular; Monitor; Morbidity - disease rate; Multiple Myeloma; Mus; Organ; Pathway interactions; Patients; Phase; Play; Population; Prevention therapy; Reaction; Rodent Model; Role; STAT1 gene; STAT3 gene; Signal Pathway; Signal Transduction; Stem cell transplant; T-Lymphocyte; Testing; Therapeutic; Tissue Grafts; Tissues; Transcription Coactivator; Treatment Efficacy; Tumor Immunity; Up-Regulation; base; chemokine; conditioning; cytokine; graft versus host disease induction; graft vs host disease; graft vs host reaction; in vivo; inhibitor/antagonist; irradiation; leukemia; mortality; neoplastic cell; novel strategies; prevent; programs; public health relevance; response; small molecule; tumor growth

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.

描述（由申请人提供）：由于移植物抗白血病（GVL）效应，同种异体血液或骨髓移植（BMT）是一种非常有效和潜在的治疗许多造血恶性肿瘤的方法。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了供体T细胞向GVHD靶器官的募集（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为未来的靶向治疗和预防GVHD提供新的方法。Janus Kinase (JAK) - Signal activator of transcription （STAT）通路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通路。使用同种异体BMT的啮齿动物模型，我们已经确定STAT1和STAT3的激活是GVHD靶器官诱导GVHD的早期事件。我们认为，STAT1和STAT3是GVHD靶器官炎症的必需介质，反过来，STAT1和STAT3可能拮抗GVL效应。因此，测试STAT1和STAT3在GVHD和GVL中的作用是本提案的主要目标。在Aim 1中，我们将使用组成型STAT1或条件型STAT3基因缺陷小鼠以及STAT1和STAT3的小分子抑制剂，研究STAT1和STAT3作为GVHD添加介质的需求。在不同的免疫遗传宿主-供体差异以及非条件小鼠中，GVHD将在致死照射后诱导。此外，使用STAT1或STAT3基因缺陷小鼠，我们将剖析宿主与供体STAT1/3对GVHD发展的需求。在Aim 2中，我们将研究STAT1和STAT3在调节淋巴造血GVH反应和GVL效应中的作用，在没有或存在条件诱导炎症的情况下，并将解决STAT1或STAT3的操纵是否会增强GVL效应的问题。公共卫生相关性：同种异体造血干细胞移植是治疗多种良性和恶性造血系统疾病的首选方法。移植物抗宿主病（GVHD）及其并发症仍然是异体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或感染并发症，从而阻碍了这种潜在的治愈性治疗方案的广泛应用。因此，开发能够维持移植物抗白血病（GVL）反应，但减少或预防GVHD的新方法具有重要意义。