Dendritic Cell Subsets and Paths of Maturation in GVHD

异基因干细胞移植(AllSCT)是治疗恶性血液病的救命药物。 遗传性疾病，如镰状细胞性贫血和地中海贫血。同种异体干细胞移植中的T细胞发挥两个关键作用 作用：1)它们重建成人的T细胞免疫，由于胸腺退化，没有明显的发展 捐赠者干细胞来源的T细胞的数量；以及2)它们介导了抗肿瘤效应。不幸的是， 供者T细胞也会引起移植物抗宿主病(GVHD)，即供者T细胞对受体的攻击 纸巾。因此，所有患者都接受GVHD预防，方法是去除同种异体移植物中的T细胞或 会损害T细胞功能的药物。然而，移植物抗宿主病和传染性并发症 免疫抑制是异基因干细胞移植发病的主要原因。专业抗原提呈细胞 (APC)通过激活稀有的同种异体反应性T细胞来启动同种免疫T细胞反应。几个功能 区分移植中的抗原提呈。首先，异基因干细胞移植的受者对供体和宿主来说是嵌合的 APC。到目前为止，我们的工作重点是确定供体和宿主APC在GVHD中的不同角色 发病机制。其次，DC由一组不同的细胞组成，这些细胞具有重叠但不同的属性，并且 这些DC亚群的角色在移植模型中没有很好的定义。第三，也许也是最多的 对本应用很重要的是，DC在适应性免疫中的当前范式，其中病原体来源 模式相关分子模式受体(特别是Toll样受体)的配体， 刺激未成熟的DC成熟并迁移到次级淋巴结，可能不适用于异基因SCT 目前尚无特定的感染性病原体，诱导DC成熟的信号尚不清楚。在这 我们计划使用试剂和基因缺陷小鼠的组合来定义关键的APC亚群 GVHD，它们的成熟途径，并将检验它们的调节可以改变同种免疫的假设 为了治疗上的收获。

Allogeneic stem cell transplantation (alloSCT) is life-saving therapy for hematologic malignancies and inherited disorders such as sickle cell anemia and thalassemia. T cells in alloSCT grafts play two pivotal roles: 1) they reconstitute T cell immunity in adults who, due to thymic involution, do not develop significant numbers of donor stem cell-derived T cells; and 2) they mediate an antineoplastic effect. Unfortunately, donor T cells also cause Graft-vs.-Host Disease (GVHD), the attack of donor T cells against recipient tissues. Therefore, all patients receive GVHD prophylaxis either via depletion of T cells from the allograft or with agents that impair T cell function. Nevertheless, GVHD and the infectious complications of immunosuppression are the major causes of morbidity in alloSCT. Professional antigen presenting cells (APCs) initiate alloimmune T cell responses by priming rare alloreactive T cells. Several features distinguish antigen presentation in transplantation. First, alloSCT recipients are chimeric for donor and host APCs. Our work to date focused on characterizing the distinct roles for donor and host APCs in GVHD pathogenesis. Second, DCs comprise a diverse set of cells with overlapping but distinct properties and the roles for these DC subsets are not well defined in transplantation models. Third and perhaps most important to the present application, the current paradigm for DCs in adaptive immunity, in which pathogenderived ligands for pattern associated molecular pattern receptors (in particular Toll-like receptors), stimulate immature DCs to mature and migrate to secondary lymph nodes, may not apply in alloSCT where there are no specific infectious pathogens and signals that induce DC maturation are unknown. In this proposal we plan to use a combination of reagents and gene deficient mice to define critical APC subsets in GVHD, their pathways of maturation, and will test the hypothesis that their modulation can alter alloimmunity for a therapeutic gain.