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）：同种异体血液或骨髓移植（BMT）是由于相关的移植物与白血病（GVL）效应引起的许多造血恶性肿瘤的高效且潜在的治疗方法。但是，这种有益的GVL效应经常被移植与宿主疾病（GVHD）的发展所抵消。 GVHD的发展至关依赖于GVHD目标器官中的系统性和局部炎症反应。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细胞募集到GVHD靶器官（例如，粘附分子的上调，趋化因子上调）和诱导组织损伤。因此，鉴定信号通路和候选分子可能会导致对未来靶向治疗和预防GVHD的新方法。 Janus激酶（JAK） - 转录（STAT）途径的信号激活因子是一种主要的信号通路，将细胞因子信号转换为调节促促促疾病和抗炎反应的基因表达程序。使用同种异体BMT的啮齿动物模型，我们确定STAT1和STAT3的激活是GVHD目标器官GVHD期间的早期事件。我们建议STAT1和STAT3是GVHD目标器官中炎症的介体，相反，STAT1和STAT3可能会拮抗GVL效应。因此，该提案测试STAT1和STAT3在GVHD和GVL中的作用是该提案的主要目标。在AIM 1中，我们将使用本构STAT1或有条件的STAT3基因缺陷小鼠和STAT1和STAT3的小分子抑制剂来研究STAT1和STAT3作为GVHD添加的介体的要求。在不同的免疫宿主 - 抑制差异以及无条件的小鼠中，将在致命照射后引起GVHD。此外，使用STAT1或STAT3基因缺乏小鼠，我们将剖析宿主与供体STAT1/3的需求对GVHD的开发。在AIM 2中，我们将研究STAT1和STAT3在不存在或存在条件引起的炎症的情况下调节淋巴瘤的GVH反应和GVL效应中的作用，并将解决对STAT1或STAT3的操纵是否可能增强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造血系统多种恶性和良性疾病的选择治疗。移植物与宿主疾病（GVHD）及其并发症仍然是同种异体干细胞移植后发病率和死亡率的主要原因。 15％至50％的患者因GVHD或感染并发症而死亡，并排除了这种潜在的治疗方法的广泛应用。因此，开发新的方法具有很高的意义，这些方法可以维持移植物与白血病（GVL）反应，但会减少或预防GVHD。