Bcl-2 作为人类肾小管间质性炎症的治疗靶点。
Bcl-2 as a Therapeutic Target in Human Tubulointerstitial Inflammation.
机构信息
University of Chicago, Chicago, Illinois.
Stuart Perper, BS, Susan Westmoreland, VMD, Lisa Olson, PhD, Li Chun Wang, PhD: AbbVie, AbbVie Bioresearch Center, Worcester, Massachusetts.
出版信息
Arthritis Rheumatol. 2016 Nov;68(11):2740-2751. doi: 10.1002/art.39744.
OBJECTIVE
In lupus nephritis, tubulointerstitial inflammation (TII) is associated with in situ adaptive immune cell networks that amplify local tissue damage. Since conventional therapy appears ineffective for severe TII, and these patients often progress to renal failure, understanding in situ mechanisms might reveal new therapeutic targets. This study was undertaken to assess whether dysregulated apoptotic regulators maintain local adaptive immunity and drive inflammation in TII.
METHODS
This study utilized novel computational approaches that, when applied to multicolor confocal images, quantified apoptotic regulator protein expression in selected lymphocyte subsets. This approach was validated using laser-capture microdissection (LCM) coupled to quantitative polymerase chain reaction (qPCR). Furthermore, the consequences of dysregulated apoptotic mediator expression were explored in a murine model of lupus nephritis.
RESULTS
Analyses of renal biopsy tissue from patients with lupus nephritis and those with mixed cellular renal allograft rejection revealed that the B cell lymphoma 2 protein (Bcl-2) was frequently expressed in infiltrating lymphocytes, whereas expression of myeloid cell leukemia 1 was low. In contrast, the reciprocal pattern of expression was observed in tonsil germinal centers. These results were consistent with RNA expression data obtained using LCM and qPCR. Bcl-2 was also highly expressed in tubulointerstitial infiltrates in (NZB × NZW)F1 (NZB/NZW) mice. Furthermore, treatment of NZB/NZW mice with ABT-199, a selective oral inhibitor of Bcl-2, prolonged survival and prevented proteinuria and development of TII in a lupus prevention model. Interestingly, glomerular immune complexes were partially ameliorated by ABT-199 treatment, and serum anti-double-stranded DNA antibody titers were unaffected.
CONCLUSION
These data demonstrate that Bcl-2 is an attractive therapeutic target in patients with lupus nephritis who manifest TII.
目的
在狼疮肾炎中，肾小管间质性炎症（TII）与原位适应性免疫细胞网络有关，这些细胞网络会放大局部组织损伤。由于常规治疗似乎对严重的 TII 无效，而且这些患者经常进展为肾衰竭，因此了解原位机制可能会揭示新的治疗靶点。本研究旨在评估失调的凋亡调节剂是否维持局部适应性免疫并驱动 TII 中的炎症。
方法
本研究利用了新的计算方法，当应用于多色共聚焦图像时，可定量分析选定淋巴细胞亚群中凋亡调节剂蛋白的表达。该方法通过激光捕获显微切割（LCM）与定量聚合酶链反应（qPCR）相结合进行了验证。此外，还在狼疮肾炎的小鼠模型中探索了失调的凋亡介质表达的后果。
结果
对狼疮肾炎和混合细胞性肾同种异体移植排斥患者的肾活检组织进行分析显示，B 细胞淋巴瘤 2 蛋白（Bcl-2）在浸润淋巴细胞中频繁表达，而髓样细胞白血病 1（Myeloid cell leukemia 1，Mcl-1）的表达水平较低。相比之下，在扁桃体生发中心观察到相反的表达模式。这些结果与使用 LCM 和 qPCR 获得的 RNA 表达数据一致。Bcl-2 在（NZB×NZW）F1（NZB/NZW）小鼠的肾小管间质浸润中也高度表达。此外，在狼疮预防模型中，用 Bcl-2 的选择性口服抑制剂 ABT-199 治疗 NZB/NZW 小鼠可延长其生存期，防止蛋白尿和 TII 的发生。有趣的是，ABT-199 治疗部分改善了肾小球免疫复合物，而血清抗双链 DNA 抗体滴度不受影响。
结论
这些数据表明，Bcl-2 是表现出 TII 的狼疮肾炎患者的一个有吸引力的治疗靶点。
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