A Novel Type of Dendritic Cell in Prevention of Glomerulonephritis

描述(申请人提供)：自身免疫性抗肾小球基底膜肾炎(GN)目前是无法治愈的。我们的目标是阐明这种疾病的发病机制，这可能会导致开发一种新的治疗策略。在我们的抗GBM GN大鼠模型中，LEW大鼠从早期炎症中自发恢复。对这种自然发生的恢复机制的观察导致了我们目前的研究假设：一种新型的肾小球浸润性CD8+DC(Gil CD8+DC)通过抗原递呈诱导自身反应性T细胞的凋亡来终止肾小球的自身免疫损伤；该机制的失败导致了无法控制的肾小球损伤，就像在GN易感的WKY大鼠中看到的那样。在过去的3年里，我们验证了我们的假设。首先，我们证明了GIL CD8+DC通过其细胞内的Fas-L诱导T细胞的凋亡。第二，及时向肾小球内渗透Gil CD8+DC对肾小球的恢复起决定性作用。第三，我们确定了IL-CD8+DC的谱系，并鉴定了其前体细胞。最重要的是，转移LEW大鼠GIL CD8+DC的PBL前体细胞可治愈GN易感WKY大鼠的GN。因此，GIL CD8+DC缺陷与WKY大鼠肾小球肾炎有关。此外，我们的初步数据表明，WKY大鼠GIL CD8+DC前体中几种白细胞转运相关分子的表达缺陷可能是导致延迟的原因。因此，在大鼠身上模拟这种自然恢复机制可能会导致一种潜在的人类自身免疫性肾炎的免疫治疗。我们推测白细胞转运相关分子在GIL CD8+DC和炎症肾小球中的及时表达控制着及时的渗透。这一新的应用将研究CD8+DC如何及时渗透肾小球，重点是在AIMS 1和3中PBL CD8+前体和炎症肾小球中的白细胞转运相关分子。我们将进一步测试通过基因操作增强细胞的及时渗透能力是否能治愈GN易感WKY大鼠的GN(AIM 2)。这些目标的实现不仅将揭示发生在靶器官的独特的免疫耐受机制，而且将为自身免疫性肾炎细胞免疫治疗的发展提供一个可操作的模型。

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.