A Novel Type of Dendritic Cell in Prevention of Glomerulonephritis

描述(申请人提供)：本申请旨在研究一种新的机制，通过该机制，一种新发现的CD8aa CD11表型的树突状细胞(DC)通过诱导引起肾小球损伤的自体T细胞的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，但单靠致病T细胞还不足以导致这种疾病。例如，在我们的抗GBM肾小球肾炎(GN)模型中，WKY大鼠的疾病是由胶原蛋白4a3链的一个强大的致肾病T细胞表位pCol(2840)诱发的。然而，卢大鼠具有相同的MHC，对pCol(2840)的T细胞反应相似，对GN诱导具有抵抗力。为了明确与肾炎易感性相关的机制，我们首先在LEW大鼠的肾小球中发现了一过性T细胞介导的炎症，这与一种新型的CD8aa CD11树突状细胞向肾小球的渗透相一致。进一步研究表明，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。相反，在GN易感的WKY大鼠中，DC的渗透发生在更晚的阶段，此时肾小球损害已经加剧。因此，LEW的GN抵抗是由于含有进一步肾小球损害的新型DC的早期渗透所致。我们的发现揭示了一种新的自我耐受机制，用于在激活的T细胞启动组织损伤后控制自身免疫性疾病。这可能有助于开发抗GBM GN发病后的新治疗策略。 我们推测，新的CD8aa CD11树突状细胞是维持自身耐受的关键，它通过及时渗透靶组织和诱导自身反应性T细胞的凋亡来维持自身耐受。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说。首先，我们将确定DC诱导的是哪条凋亡途径，以及对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，以及这是否与GN易感性有关。第三，我们将测试肾小球微环境是否对DC的及时渗透负责。公共卫生相关性抗GBM肾小球肾炎是一种人类自身免疫性疾病，到目前为止，是无法治愈的。利用动物模型，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。我们满怀希望，我们的研究可能有助于该病发病后治疗策略的制定。

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.