LIGHT co-stimulatory therapy on GVHD and GVL

描述（由申请人提供）：移植物抗宿主病（GVHD）是由协调的宿主反应性供体T细胞反应引起的，仍然是异基因骨髓移植（BMT）或造血干细胞移植的主要并发症。虽然GVHD可以通过T细胞免疫的全面抑制或供体T细胞耗竭来减弱，但这些治疗也消除了针对残留肿瘤或感染性病原体的有益供体T细胞应答。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。LIGHT-HVEM信号的消除抑制了亲代小鼠F1移植小鼠GVHD模型中同种异体反应性CTL的产生，而它不损害疫苗诱导的对标称抗原的CTL应答。该建议的中心假设是阻断LIGHT-HVEM途径可以预防GVHD而不需要全面的免疫抑制。因此，这种方法将被开发用于治疗临床GVHD并维持移植物抗白血病（GVL）效应。为了检验这一假设，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，例如由MHC匹配、轻微组织相容性Ag不匹配的BMT诱导的那些。其次，探讨LIGHT-HVEM共刺激通路相关分子BTLA和LTbR在GVHD中的作用。最后，将测试LIGHT-HVEM阻断和抗肿瘤DC疫苗的组合疗法以治疗GVHD同时介导GVL效应。本研究为LIGHT-HVEM阻断治疗白血病异基因骨髓移植相关GVHD和GVL的临床应用奠定了基础。移植物抗宿主病（GVHD）是骨髓移植后最严重的并发症之一。在本项目中，我们将通过操纵辅助信号分子LIGHT来发现新的GVHD免疫治疗方法。

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.