LIGHT co-stimulatory therapy on GVHD and GVL

移植物抗宿主病(GVHD)是由有组织的宿主反应性供者T细胞反应和 仍然是异基因骨髓移植(BMT)或造血干细胞的主要并发症 移植。虽然GVHD可以通过整体抑制T细胞免疫或供者T细胞来减弱 耗尽，这些治疗也取消了有益的捐赠者T细胞对残留肿瘤或 传染性病原体。我们的长期目标是寻找选择性免疫干预的方法 抑制移植物抗宿主病，同时避免T细胞对癌症和病原体的反应。我们的初步数据显示 LIGH-HVEM是一条有效的共刺激途径，是GVHD发生的先决条件。 去除LIGH-HVEM信号抑制亲本同源反应性CTL的产生 小鼠移植物抗宿主病(GVHD)模型，但不损害疫苗诱导的针对名义抗原的CTL反应。这个 这一建议的中心假设是，阻断Light-HVEM通路可以预防GVHD而不需要 全球免疫抑制。因此，这一方法将被开发用于临床GVHD的治疗和维持 移植物抗白血病(GVL)效应。为了验证这一假设，我们首先将光-紫外线封锁建立为 对临床相关GVHD模型的有效免疫治疗，如MHC相合、Minor诱导的模型 组织相容性银不相合骨髓移植。第二，BTLA和LTbR相关分子的功能作用 光-HVEM共刺激通路在移植物抗宿主病中的作用将被探索。最后，综合疗法 光-HVEM阻断和抗肿瘤DC疫苗将用于治疗GVHD，同时介导GVL效应。 本研究将为今后光-高压电封闭疗法的临床应用奠定基础。 移植物抗宿主病和移植物抗宿主病在白血病患者异基因骨髓移植中的应用。 移植物抗宿主病(GVHD)是继骨髓之后最危及生命的并发症之一。 移植。在这个项目中，我们将通过一种新的免疫疗法发现治疗GVHD的方法 光的操纵，共信号分子的一个新成员。

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.