University of Rochester Medical Center, Rochester, New York.
Instituto Nacional de Psiquiatría Ramón de la Fuente, Mexico City, Mexico.
Arthritis Rheumatol. 2022 Aug;74(8):1363-1375. doi: 10.1002/art.42128. Epub 2022 Jun 28.
To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus.
Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay.
KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis.
Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells.
探究选择性核输出抑制剂（SINE 化合物）的假设，这些化合物最近被批准用于治疗难治性浆细胞（PC）恶性肿瘤，可能具有治疗狼疮的潜力。
用 SINE 化合物 KPT-350 或载体对照物处理雌性 NZB/NZW 小鼠。使用标准标志物通过流式细胞术采集和分析组织标本。通过测定蛋白尿评分和肾组织学分析监测肾炎。通过酶联免疫吸附试验测量血清抗双链 DNA（抗 dsDNA）水平，并通过酶联免疫斑点试验评估总 IgG 分泌细胞和 dsDNA 特异性抗体分泌细胞的数量。
KPT-350 在疾病的早期和晚期都消除了小鼠狼疮肾炎，并迅速损害了生发中心（GC）中自身反应性 PC 的产生。SINE 化合物抑制基质细胞产生 NF-κB 驱动的稳态趋化因子，改变脾 B 和 T 细胞的战略定位，并显著减少滤泡辅助 T 细胞、GC B 细胞和自身反应性 PC 的数量。KPT-350 还降低了狼疮易感小鼠肾脏中参与 PC 存活和募集的细胞因子和趋化因子的水平。SINE 化合物的靶标出口蛋白 1，在人类扁桃体的 GC 中、狼疮患者的脾 B 细胞中和狼疮肾炎患者肾脏中的多个 B 细胞亚群中均有检测到。
总之，我们的结果为 SINE 化合物的治疗潜力提供了支持，通过其靶向狼疮发病机制中的几个分子和细胞途径，包括浆细胞产生自身抗体。
