Characterizing a New Human Dendritic Cell Lineage and Its Role in LCH

人类新树突状细胞谱系的表征及其在 LCH 中的作用

• 批准号: 8597535
• 负责人: MIRIAM MERAD
• 金额: $ 33.99万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-14 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597535
• 关键词: Address; Adjustment Disorders; Affect; Birbeck Granule; Blood; Cell Lineage; Cells; Childhood; Clinical; Copy Number Polymorphism; Data; Dendritic Cells; Dermis; Development; Diagnosis; Disabled Persons; Disease; Future; Genes; Greek; Growth Factor; Hematopoietic; Histiocytosis; Human; Human Development; Individual; Infant; Knowledge; Langerhans cell; Langerhans-Cell Histiocytosis; Lead; Lesion; Ligands; Liver; Liver parenchyma; Lung; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Mus; Mutation; Nature; Neuraxis; Organ; Organ failure; Orthopedics; Pathway interactions; Patients; Phenotype; Physicians; Population; Rare Diseases; Receptor Inhibition; Research; Role; Skin; Stratified Epithelium; Structure of parenchyma of lung; System; T-Lymphocyte; Testing; Tissues; base; cohort; comparative; cytokine; deep sequencing; gene function; handicapping condition; histiocyte; human langerin; human tissue; interstitial; langerin; macrophage; monocyte; mouse model; neoplastic; new therapeutic target; prevent; progenitor; public health relevance; receptor

DESCRIPTION (provided by applicant): Langerhans Cell Histiocytosis (LCH) is the most common of histiocytosis, a group of rare diseases that involve tissue-resident macrophages and dendritic cells. Patients with single system disease require minimal treatment, but even in these patients there may be permanent, mainly orthopaedic consequences. At the other extreme and most often in young infants, the presentation is multisystemic with organ failure and can be fatal in 25% of the cases. LCH results from the accumulation of Langerhans cell-like cells also called the LCH cells. LCH cells are always associated with a local cytokine storm and a large T cell infiltrate leading to irreversible damage to several organs that include the lungs, liver, central nervous system and the skin. LCH research has been hampered by problems related to rare diseases of childhood. Individual physicians see few cases and fresh material are hard to collect. The two central questions that remain unresolved and prevent adequate therapy are: 1) what is the origin of the LCH cell and 2) is LCH a true neoplastic or a reactive disorder. Answering these questions would change the way we diagnose and treat the disease. The current paradigm suggests that LCH results from an accumulation of epidermal dendritic cells (DCs) also called "Langerhans cells" (LCs).This concept is based on observations showing that LCH lesions are infiltrated by langerin+ cells and it associated Birbeck granules, features thought to be restricted to epidermal LCs. However, it has been difficult to understand how LCs, which is normally restricted to stratified epithelia, could give rise to such a multi-focal disorder. We recently identified the presence of interstitial langerin+ DCs, independent of LCs, in most non-lymphoid tissue in mice and in human lung and dermis (Fig. 5). In contrast to langerin- DCs that derive from circulating monocytes, we found that langerin+ DCs derive from a circulating DC restricted progenitor in a Flt3 ligand dependent manner. In addition, we found that inhibition of the receptor Flt3 leads to the specific depletion of langerin+ DCs whereas langerin- DCs and LCs remain unaffected. Our preliminary data also suggest that LCH cells have a phenotype that resemble interstitial langerin+ DCs, and express high levels of Flt3. Based on these findings, we hypothesize that LCH is due to an accumulation of interstitial langerin+ DCs, and not LCs, and can be characterized by dysregulated molecular pathways in the former. We also hypothesize that the receptor Flt3 may represent a novel therapeutic target for the treatment of LCH patients. To address this hypothesis we propose in aim 1 to characterize langerin+ DCs that populate in healthy tissues in humans. In aim 2, we propose to identify the precursors and the mechanisms that control the development of human langerin+, while in Aim 3 we propose to characterize the circulating precursors and langerin+ DCs that accumulate in LCH lesions.

描述（由申请人提供）：Langerhans细胞组织细胞增多症（LCH）是最常见的组织细胞增多症，这是一组涉及组织居住的巨噬细胞和树突状细胞的稀有疾病。单个系统疾病的患者需要最少的治疗，但是即使在这些患者中，也可能存在永久性的，主要是骨科后果。在另一个极端，最常见于年轻的婴儿，演讲是多系统的，具有器官衰竭，在25％的病例中可能是致命的。 LCH是由于Langerhans细胞样细胞的积累也称为LCH细胞。 LCH细胞始终与局部细胞因子风暴和大型T细胞浸润有关，从而导致对包括肺，肝脏，中枢神经系统和皮肤在内的多个器官的不可逆转损害。 LCH研究受到与少数童年疾病有关的问题的阻碍。个人医生看到的病例很少，很难收集新鲜材料。尚未解决并预防适当治疗的两个核心问题是：1）LCH细胞的起源是什么，2）是真正的肿瘤或反应性疾病。回答这些问题将改变我们诊断和治疗疾病的方式。当前的范例表明，LCH是由表皮树突状细胞（DCS）的积累引起的，也称为“ Langerhans细胞”（LCS）。该概念是基于观察结果，表明LCH病变被Langerin+细胞渗透到Langerin+细胞及其相关的Birbeck Granules，被认为是限制为Epermal lcs的特征。但是，很难理解通常仅限于分层上皮的LC会导致这种多焦点疾病。我们最近在小鼠，人类肺和真皮中的大多数非淋巴组织中发现了间隙兰格蛋白+ DC（与LCS无关）（图5）。与从循环单核细胞中得出的兰格蛋白DC相反，我们发现Langerin+ DCS以FLT3配体依赖性方式源自循环的DC受限端祖细胞。此外，我们发现对受体FLT3的抑制会导致Langerin+ DCS的特异性耗竭，而Langerin-DCS和LCS仍未受到影响。我们的初步数据还表明，LCH细胞具有类似于间质兰格蛋白+ DC的表型，并表达高水平的FLT3。基于这些发现，我们假设LCH是由于间质兰格蛋白+ DC而不是LCS引起的，并且可以通过前者的分子途径失调而表征。我们还假设受体FLT3可能代表了治疗LCH患者的新型治疗靶点。为了解决这一假设，我们在AIM 1中提出，以表征人类健康组织中填充的Langerin+ DC。在AIM 2中，我们建议确定控制人Langerin+发展的前体和机制，而在AIM 3中，我们建议表征在LCH病变中积累的循环前体和Langerin+ DC。