Dendritic Cell Subsets and Paths of Maturation in GVHD

GVHD 中的树突状细胞亚群和成熟途径

• 批准号: 8117703
• 负责人: Warren D Shlomchik
• 金额: $ 48.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117703
• 关键词: Ablation; Adult; Alloantigen; Allogenic; Allografting; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antineoplastic Agents; Aplastic Anemia; Apoptotic; Cell physiology; Cells; Chronic; Dendritic Cells; Development; Disease; Fright; Genes; Haplotypes; Hematologic Neoplasms; Hematopoietic; Immune; Immunity; Immunosuppression; Immunotoxins; Inborn Genetic Diseases; Inflammatory Bowel Diseases; Life; Ligands; Lymphocyte; Mature T-Lymphocyte; Mediating; Modeling; Molds; Molecular; Morbidity - disease rate; Mus; Nature; Opportunistic Infections; Organ; Pathogenesis; Pathway interactions; Patients; Pattern; Play; Property; Prophylactic treatment; Reagent; Receptor Signaling; Regulatory T-Lymphocyte; Role; Secondary to; Siblings; Sickle Cell Anemia; Signal Transduction; Stem cell transplant; Stem cells; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Thalassemia; Therapeutic; Tissues; Toll-like receptors; Transgenic Mice; Transplantation; Work; adaptive immunity; apoptosis in lymphocytes; conditioning; graft vs host disease; irradiation; isoimmunity; leukemia; lymph nodes; neoplastic; novel; novel strategies; pathogen; prevent; receptor; reconstitution; response

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.

同种异体干细胞移植 (alloSCT) 是治疗血液系统恶性肿瘤和癌症的救命疗法 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移植物中的 T 细胞发挥着两个关键作用 作用：1）它们重建成人的 T 细胞免疫，由于胸腺退化，成人的 T 细胞免疫没有明显发展。 供体干细胞衍生的 T 细胞数量； 2）它们介导抗肿瘤作用。很遗憾， 供体 T 细胞还会引起移植物抗宿主病 (GVHD)，即供体 T 细胞对受体的攻击 组织。因此，所有患者都通过消除同种异体移植物中的 T 细胞或 使用损害 T 细胞功能的药物。尽管如此，GVHD 和感染并发症 免疫抑制是alloSCT 发病的主要原因。专业抗原呈递细胞 (APC) 通过启动罕见的同种异体反应性 T 细胞来启动同种免疫 T 细胞反应。几个特点 区分移植中的抗原呈递。首先，alloSCT 受体是供体和宿主的嵌合体 装甲运兵车。迄今为止，我们的工作重点是描述供体和宿主 APC 在 GVHD 中的不同作用 发病。其次，DC 包含一组不同的细胞，这些细胞具有重叠但不同的特性，并且 这些 DC 亚群的作用在移植模型中尚未明确定义。第三，也许是最多的 对本应用很重要的是，适应性免疫中 DC 的当前范例，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 成熟并迁移至二级淋巴结，可能不适用于异体干细胞移植 (alloSCT) 没有特定的传染性病原体，诱导 DC 成熟的信号也是未知的。在这个 建议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 子集 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 以达到治疗效果。