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 大鼠可以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当前资助的工作假设：一种新型肾小球浸润性 CD8 DC (GIL CD8 DC) 通过抗原呈递诱导自身反应性 T 细胞凋亡，从而终止肾小球中的自身免疫损伤；这种机制的失败会导致不受控制的肾小球损伤，正如在 GN 易感性​​ WKY 大鼠中所见。在过去的3年里，我们验证了我们的假设。首先，我们证明GIL CD8 DC通过其胞内Fas-L诱导T细胞凋亡。其次，GIL CD8 DC 及时浸润肾小球对于恢复至关重要。第三，我们描绘了 GIL CD8 DC 的谱系并在 PBL 中鉴定了其前体。最重要的是，LEW 大鼠 GIL CD8 DC 的 PBL 前体的转移治愈了 GN 易感 WKY 大鼠的 GN。因此，GIL CD8 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 CD8 DC 前体中几种白细胞运输相关分子的表达缺陷可能是造成延迟的原因。因此，模仿大鼠的这种自然恢复机制可能会为人类自身免疫性肾小球肾炎提供潜在的免疫疗法。我们假设 GIL CD8 DC 和发炎肾小球中白细胞运输相关分子的及时表达控制着及时浸润。本次更新应用将研究 CD8 DC 如何及时浸润肾小球，重点关注目标 1 和 3 中 PBL CD8 前体和发炎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 易感性​​ WKY 大鼠的 GN（目标 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，还将为开发基于细胞的自身免疫性肾小球肾炎免疫疗法提供工作模型。

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.