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: 8598160
• 负责人: YAHUAN LOU
• 金额: $ 1.42万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598160
• 关键词: Antigen Presentation; Apoptosis; Autoimmune Process; Autoimmunity; Biochemical; Biological Assay; CD8B1 gene; Cell Adhesion Molecule Gene; Cell Adhesion Molecules; Cells; Data; Defect; Dendritic Cells; Development; Disease; Failure; Fibrosis; Gene Expression; Glomerular basement membrane antibody; Glomerulonephritis; Grant; Human; Immune Tolerance; Immunotherapy; In Vitro; Inbred WKY Rats; Induction of Apoptosis; Infiltration; Inflammation; Lead; Leukocyte Trafficking; Leukocytes; Ligands; Liposomes; Mediating; Modeling; Molecular; Organ; Pathogenesis; Polysialic Acid; Population; Population Sizes; Prevention; Proteins; Rat Strains; Rattus; Receptor Cell; Recovery; Recruitment Activity; Specificity; Staging; T-Lymphocyte; Testing; Time; Tumor Necrosis Factor Ligand Superfamily Member 6; Work; base; chemokine; chemokine receptor; expression vector; genetic manipulation; in vivo; model development; novel; novel therapeutics; receptor; trafficking

DESCRIPTION (provided by applicant): Autoimmune anti-GBM glomerulonephritis (GN) is currently incurable. We aim to elucidate pathogenesis of this disease, which may lead to development of a novel therapeutic strategy. In our rat model for anti-GBM GN, LEW rats spontaneously recover from early inflammation. Observations on this naturally occurring recovery mechanism had led to our working hypothesis for the current grant: A novel glomeruli- infiltrating CD8 + DC (GIL CD8 + DC) terminated autoimmune damage in glomeruli by inducing apoptosis in self-reactive T cells through antigen presentation; failure in this mechanism led to uncontrolled glomerular damage as seen in GN-susceptible WKY rats. In the past 3 years, we have verified our hypothesis. First, we demonstrated that GIL CD8 + DC induced apoptosis in T cells by its intracellular Fas-L. Second, timely infiltration of GIL CD8 + DC into glomeruli was decisive for the recovery. Third, we delineated the lineage of GIL CD8 + DCs and identified its precursor in PBL. Most importantly, transfer of PBL precursor of GIL CD8 + DCs of LEW rats cured GN in GN-susceptible WKY rats. Thus, defects in GIL CD8 + DCs are responsible for GN in WKY rats. In addition, our preliminary data suggested that defect in expression of several leukocyte- trafficking related molecules in precursor of GIL CD8 + DCs in WKY rats may be responsible for the delay. Thus, mimicking this natural recovery mechanism in rats may lead to a potential immunotherapy for human autoimmune GN. We hypothesize that timely expression of leukocyte trafficking related molecules in both GIL CD8 + DC and inflamed glomeruli governs timely infiltration. This renewal application will investigate how the CD8 + DCs timely infiltrate glomeruli with emphasis on leukocyte trafficking related molecules in both PBL CD8 + precursor and inflamed glomeruli in Aims 1 and 3. We will further test if enhancing the cell's ability in timely infiltration through genetic manipulation will cure GN in GN-susceptible WKY rats (Aim 2). Accomplishment of those aims will not only reveal a unique immune tolerance mechanism occurring in the target organ, but also provide a working model for development of cell-based immunotherapy for autoimmune GN.

描述（由申请方提供）：自身免疫性抗GBM肾小球肾炎（GN）目前无法治愈。我们的目的是阐明这种疾病的发病机制，这可能会导致一种新的治疗策略的发展。在我们的抗GBM GN大鼠模型中，LEW大鼠自发地从早期炎症中恢复。对这种自然发生的恢复机制的观察导致了我们对当前资助的工作假设：一种新的肾小球浸润性CD 8 + DC（GIL CD 8 + DC）通过抗原呈递诱导自身反应性T细胞凋亡来终止肾小球中的自身免疫损伤;这种机制的失败导致了不受控制的肾小球损伤，如在GN敏感的WKY大鼠中所见。在过去的三年里，我们已经验证了我们的假设。首先，我们证明GIL CD 8 + DC通过其细胞内的Fas-L诱导T细胞凋亡。第二，GIL CD 8 + DC及时浸润到肾小球是恢复的决定性因素。第三，我们描述了GIL CD 8 + DC的谱系，并在PBL中鉴定了其前体。最重要的是，移植LEW大鼠GIL CD 8 + DCs的PBL前体治疗GN敏感WKY大鼠的GN。因此，GIL CD 8 + DC的缺陷是WKY大鼠GN的原因。此外，我们的初步数据表明，WKY大鼠GIL CD 8 + DC前体中几种白细胞运输相关分子的表达缺陷可能是导致延迟的原因。因此，在大鼠中模仿这种自然恢复机制可能会导致人类自身免疫性GN的潜在免疫疗法。我们推测，及时表达白细胞运输相关分子在GIL CD 8 + DC和炎症肾小球及时浸润。本更新申请将研究CD 8 + DC如何及时浸润肾小球，重点是PBL CD 8+前体和炎症肾小球中的白细胞运输相关分子，目的1和3。我们将进一步测试通过遗传操作增强细胞及时渗透的能力是否会治愈GN敏感WKY大鼠中的GN（目的2）。这些目标的实现不仅将揭示靶器官中发生的独特免疫耐受机制，而且还将为开发基于细胞的自身免疫性GN免疫治疗提供工作模型。