A Novel Type of Dendritic Cell in Prevention of Glomerulonephritis

预防肾小球肾炎的新型树突状细胞

• 批准号: 7602997
• 负责人: YAHUAN LOU
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602997
• 关键词: Accounting; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological Assay; Bone Marrow; CD11 Antigens; COS Cells; Cell physiology; Cells; Chimera organism; Collagen; DNA; Defect; Dendritic Cells; Development; Disease; Disease model; Flow Cytometry; Gene Expression; Genes; Glomerular basement membrane antibody; Glomerulonephritis; Human; Immune response; In Vitro; Inbred WKY Rats; Individual; Induction of Apoptosis; Infiltration; Inflammation; Lead; Link; Maintenance; Mediating; Modeling; Molecular Profiling; Pathogenesis; Pathway interactions; Phenotype; Population; Predisposition; Prevention; Rattus; Research; Resistance; Role; Self Tolerance; Staging; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Tissues; Tumor Necrosis Factor Ligand Superfamily Member 6; chemokine; chemokine receptor; disorder control; in vitro testing; in vivo; neutralizing antibody; novel; novel therapeutics; prevent; public health relevance; response; therapeutic development

DESCRIPTION (provided by applicant): This application intends to investigate a novel mechanism, by which a newly discovered dendritic cell (DC) of CD8aa + CD11 + phenotype prevents glomerular autoimmune damage by the induction of apoptosis of selfreactive T cells that are causing glomerular damage. Despite their critical role in many autoimmune diseases, pathogenic T cells alone are not sufficient to cause the disease. For example, in our antiGBM glomerulonephritis (GN) model, the disease is induced in WKY rats by a potent nephritogenic T cell epitope pCol(2840) of collagen 4a3 chain. However, LEW rats, which have identical MHC and mount a similar T cell response to pCol(2840), are resistant to GN induction. To define the mechanism associated with GN susceptibility, we first found a transient T cell mediated inflammation in the glomeruli of LEW rats, coincident with infiltration of a novel type of CD8aa + CD11 + DC into the glomeruli. Further studies showed that this glomerular infiltrating DC actively induced a non FasL mediated apoptosis in self reactive T cells through its antigen presentation. In contrast, infiltration of the DC occurred at a much later stage in GN susceptible WKY rats, when glomerular damage had advanced. Therefore, GN resistance in LEW is due to early infiltration of the novel DC which contains further glomerular damage. Our finding reveals a novel self tolerance mechanism for controlling autoimmune diseases after activated T cells initiate tissue damage. This may aid development of new therapeutic strategies for antiGBM GN after its onset. We hypothesize that the novel CD8aa + CD11 + DC is critical for maintenance of self tolerance through its timely infiltration of target tissue and induction of apoptosis of self reactive T cell. In this application, we will fulfill three specific aims to further define this hypothesis. First, we will determine which apoptosis pathway is induced by the DC and whether manipulation of apoptosis would alter GN susceptibility. Second, we will determine whether the DC in WKY is dysfunctional, and whether this is responsible for GN susceptibility. Third, we will test whether glomerular microenvironment is responsible for timely infiltration of the DC. PUBLIC HEALTH RELEVANCE Anti-GBM glomerulonephritis is a human autoimmune disease that, as of now, is incurable. Using an animal model, we propose to investigate how a special type of dendritic cells control this disease after the tissue damage has begun. With high hopes, our study may aid the development of therapeutic strategies for the disease after its onset.

描述（由申请人提供）：本申请旨在研究一种新的机制，通过该机制，新发现的具有CD8aa + CD11 +表型的树突状细胞（DC）通过诱导引起肾小球损伤的自身反应性T细胞凋亡来预防肾小球自身免疫损伤。尽管它们在许多自身免疫性疾病中起着关键作用，但致病性T细胞本身并不足以引起疾病。例如，在我们的抗GBM肾小球肾炎（GN）模型中，该疾病在WKY大鼠中由胶原4a3链的有效致肾炎性T细胞表位pCol（2840）诱导。然而，LEW大鼠具有相同的MHC，并对pCol（2840）产生类似的T细胞应答，对GN诱导具有抗性。为了确定与GN易感性相关的机制，我们首先在LEW大鼠的肾小球中发现了一种短暂的T细胞介导的炎症，与一种新型的CD8aa + CD11 + DC浸润到肾小球中一致。进一步的研究表明，这种肾小球浸润性DC通过其抗原提呈主动诱导自身反应性T细胞的非FasL介导的凋亡。相比之下，浸润的DC发生在一个更晚的阶段，在GN易感的WKY大鼠，当肾小球损伤已经进展。因此，LEW中的GN抗性是由于包含进一步肾小球损伤的新型DC的早期浸润。我们的发现揭示了一种新的自身耐受机制，用于在激活的T细胞引发组织损伤后控制自身免疫性疾病。这可能有助于抗GBM GN发病后新的治疗策略的发展。 我们推测新的CD8aa + CD11 + DC通过其及时的靶组织浸润和诱导自身反应性T细胞凋亡在维持自身耐受中起关键作用。在本申请中，我们将实现三个具体目标，以进一步定义这一假设。首先，我们将确定哪种凋亡途径是由DC诱导的，以及细胞凋亡的操纵是否会改变GN的易感性。其次，我们将确定WKY中的DC是否功能失调，以及这是否是GN易感性的原因。第三，我们将测试肾小球微环境是否负责DC的及时浸润。抗GBM肾小球肾炎是一种人类自身免疫性疾病，目前尚无法治愈。使用动物模型，我们建议研究一种特殊类型的树突状细胞如何在组织损伤开始后控制这种疾病。满怀希望，我们的研究可能有助于开发疾病发作后的治疗策略。