A Novel Type of Dendritic Cell in Prevention of Glomerulonephritis

描述（由申请人提供）：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对当前资助的工作假设：一种新的肾小球浸润性CD8 + DC （GIL CD8 + 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的自身免疫损伤；在gn易感的WKY大鼠中，这一机制的失败导致肾小球不受控制的损伤。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 CD8 + DC通过其细胞内Fas-L诱导T细胞凋亡。其次，GIL CD8 + DC及时浸润肾小球是恢复的决定性因素。第三，我们描绘了GIL CD8 + dc的谱系，并确定了其在PBL中的前体。最重要的是，LEW大鼠GIL CD8 + dc的PBL前体的转移治愈了GN易感的WKY大鼠的GN。因此，GIL CD8 + dc缺陷是WKY大鼠GN发生的原因。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，在大鼠中模拟这种自然恢复机制可能会导致人类自身免疫性GN的潜在免疫治疗。我们假设GIL CD8 + DC和炎症肾小球中白细胞运输相关分子的及时表达控制了及时浸润。在Aims 1和Aims 3中，我们将研究CD8 + dc如何及时浸润肾小球，重点研究PBL CD8 +前体和炎症肾小球中的白细胞运输相关分子。我们将进一步测试通过基因操作增强细胞及时浸润的能力是否可以治愈GN易感的WKY大鼠的GN （Aim 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，而且还将为自身免疫性GN的细胞免疫治疗的发展提供一个工作模型。

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. PUBLIC HEALTH RELEVANCE: Autoimmune anti-GBM glomerulonephritis is currently incurable. A rat strain shows spontaneous recovery from this disease. We aim to elucidate why a novel CD8 + DC-like cell is critical for the recovery, and further to test if mimicking this natual recovery mechanism can be applied for a cell-based immunotherapy for this disease.