LIGHT co-stimulatory therapy on GVHD and GVL

LIGHT 共刺激治疗 GVHD 和 GVL

• 批准号: 7835566
• 负责人: KOJI TAMADA
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-10 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835566
• 关键词: Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Attenuated; Binding; Bone Marrow Transplantation; Clinical; Combined Modality Therapy; Complication; Data; Dendritic Cell Vaccine; Development; Disease model; Foundations; Future; Generations; Genes; Goals; Hematopoietic Stem Cell Transplantation; Histocompatibility; Immunity; Immunosuppression; Immunotherapy; Knockout Mice; Laboratories; Life; Malignant Neoplasms; Mediating; Methods; Minor; Modeling; Mus; Parents; Pathway interactions; Patients; Research Personnel; Residual Tumors; Residual state; Role; Signal Transduction; Signaling Molecule; T cell regulation; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Transplantation; Treatment Efficacy; Tumor Necrosis Factor-Beta; Vaccines; clinical application; clinically relevant; graft vs host disease; high voltage electron microscopy; immunological intervention; leukemia; member; mutant; neutralizing monoclonal antibodies; novel; pathogen; prevent; programs; receptor; response; tumor

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is caused by orchestrated host-reactive donor T cell responses and remains a major complication of allogeneic bone marrow transplantation (BMT) or hematopoietic stem cell transplantation. Although GVHD can be attenuated by global suppression of T cell immunity or donor T cell depletion, these treatments also abrogates beneficial donor T cell responses against residual tumors or infectious pathogens. Our long-term goal is to seek the methods for immunological intervention that selectively inhibits GVHD while sparing T cell responses to cancers and pathogens. Our preliminary data demonstrate that LIGHT-HVEM is a potent co-stimulatory pathway which is prerequisite for the generation of GVHD. Abrogation of LIGHT-HVEM signal inhibits the generation of allo-reactive CTL in parent into F1 transplantation mouse GVHD model, whereas it does not impair vaccine-induced CTL responses to nominal antigens. The central hypothesis of this proposal is that blockade of LIGHT-HVEM pathway can prevent GVHD without a global immune suppression. Therefore, this approach will be developed to treat clinical GVHD and to maintain graft-versus-leukemia (GVL) effect. To test this hypothesis, we will first establish LIGHT-HVEM blockade as a efficient immunotherapy for clinically relevant GVHD models such as those induced by MHC-matched, minor histocompatibility Ag-mismatched BMT. Second, functional role of BTLA and LTbR, molecules related with LIGHT-HVEM co-stimulatory pathway, in GVHD will be explored. Finally, combination therapy of LIGHT-HVEM blockade and anti-tumor DC vaccine will be tested to treat GVHD while mediating GVL effects. This study will lay the foundation for the development of LIGHT-HVEM blockade therapy as future clinical applications in GVHD and GVL associated with allogeneic BMT for leukemia patients. Graft-versus-host disease (GVHD) is one of the most life-threatening complications after bone marrow transplantation. In this project, we will discover novel immunological therapies for GVHD through a manipulation of LIGHT, a recent member of co-signal molecule.

描述（由申请人提供）：移植物抗宿主病（GVHD）是由宿主反应性供体T细胞反应引起的，是同种异体骨髓移植（BMT）或造血干细胞移植的主要并发症。虽然GVHD可以通过整体抑制T细胞免疫或供体T细胞耗竭来减弱，但这些治疗也会消除有益的供体T细胞对残留肿瘤或感染性病原体的反应。我们的长期目标是寻求免疫干预的方法，选择性地抑制GVHD，同时保留T细胞对癌症和病原体的反应。我们的初步数据表明，LIGHT-HVEM是一种有效的共刺激途径，是GVHD产生的先决条件。在F1移植小鼠GVHD模型中，去除LIGHT-HVEM信号可抑制亲本体内同种异体反应性CTL的产生，而不影响疫苗诱导的CTL对标称抗原的反应。该建议的中心假设是，阻断LIGHT-HVEM通路可以在不全局免疫抑制的情况下预防GVHD。因此，这种方法将用于治疗临床GVHD和维持移植物抗白血病（GVL）的效果。为了验证这一假设，我们将首先建立LIGHT-HVEM阻断作为临床相关GVHD模型的有效免疫疗法，例如mhc匹配，轻度组织相容性ag不匹配的BMT诱导的GVHD模型。其次，探讨与LIGHT-HVEM共刺激通路相关的分子BTLA和LTbR在GVHD中的功能作用。最后，我们将测试LIGHT-HVEM阻断和抗肿瘤DC疫苗联合治疗GVHD并介导GVL效应。该研究将为LIGHT-HVEM阻断疗法的发展奠定基础，作为未来临床应用于白血病患者同种异体BMT相关的GVHD和GVL。移植物抗宿主病（GVHD）是骨髓移植后最严重的并发症之一。在这个项目中，我们将通过操纵共同信号分子的新成员LIGHT来发现新的GVHD免疫治疗方法。