Background/Purpose:

There is great interest in developing new treatment approaches for SLE, but the biologic therapies under investigation over the past several years have yielded disappointing results.  SINE are orally available, well tolerated XPO1 (Exportin 1/CRM1) antagonists that are in human phase 1 clinical trials and show potent activity and tolerability in hematologic malignancies. We hypothesized that SINE would be efficacious in murine lupus through the combined targeting of interferon alpha production by plasmacytoid dendritic cells (pDCs) and autoantibody production by plasma cells (PCs). 

Methods:

Nephritic NZB/W F1 lupus-prone female mice, with elevated serum anti-dsDNA antibodies and established proteinuria, were treated with the SINE KPT-251 or vehicle control by oral gavage (n=9 per group).  Proteinuria was monitored, and kidney histology assessed (0-4+ scale). Spleen, bone marrow (BM), and kidney were harvested, cells analyzed by flow cytometry, and antibody secreting cells (ASCs) enumerated by ELIspot. Serum samples and RNA were collected for Luminex assay and qPCR. Effects on pDC production of IFN were assessed using in-vitro cultures with BM cells stimulated with CpG 2216 10ng/ml for 5 hours. 

Results:

SINEs inhibit the production of IFN alpha by pDCs in a dose dependent fashion: pDC% positive for IFN no drug 10.5%, 3.125 uM 12.1%, 6.25 um 9%, 12.5 um 3.8%, and 25 uM 1.2%. IFN regulated chemokines in the serum of SINE treated lupus mice were decreased (MCP-1: 250+/-290 pg/ml vehicle vs. 54+/-26 pg/ml SINE, p=0.049), as was the PC survival factor IL6 (192+/-50 pg/ml vehicle vs. 11+/-23 pg/ml SINE, p=0.045). SINEs prevented nephritis progression with a statistically significant reduction in urine protein levels in the treated group (p<0.05 beginning at 5 weeks) and significantly reduced both IgG and anti-DNA ASCs in the spleen (81% reduction for anti-DNA, p=0.0048) and BM (63% reduction for anti-DNA, p=0.07).  In the spleen, GC B cells (PNA+FAS+) and T follicular helper cells (CD4+CXCR5+ICOS+PD1+) were dramatically reduced (p =0.0016 and p=0.0051, respectively). Moreover, nephritis was improved histologically (GN score 3.3+/-1.2 vehicle vs. 1.0+/-0 SINE; lymphoid infiltrate score 1.3+/-0.6 vehicle vs. 0+/- SINE). There was also a dramatic reduction in autoreactive PCs in the kidney (98% reduction for anti-DNA, p<0.0001). We are presently examining the kidney tissue for IFN regulated genes and PC survival factors.

Conclusion:

The combined reduction in IFN activation, GCs, and autoreactive plasma cells suggests that SINEs alter both the generation of PCs and the kidney PC niche with beneficial effects on nephritis. The mechanisms underlying these effects, including potential inhibition of NFkB signaling, are under investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-selective-inhibitors-of-nuclear-export-sine-decrease-type-i-interferon-activation-and-deplete-autoreactive-plasma-cells-in-the-kidney-in-murine-lupus/