Background/Purpose:  Most therapies currently used to treat systemic lupus erythematosus (SLE) and B cell targeted therapies under development do not effectively target plasma cells and autoantibodies.  We postulated that selective inhibition of nuclear export (SINE) with novel small molecule CRM1 antagonists, which have demonstrated potent activity for hematologic malignancies, may be useful in the treatment of SLE by targeting plasma cells and other immune cells critical to disease pathogenesis.

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 (injections 5/7 days for 5 weeks) (initially 75 mg/kg x 3 weeks and then 50 mg/kg for 2 additional weeks) or vehicle control subcutaneously (n=10 per group).  Spleen and bone marrow (BM) lymphocytes were harvested, stained with antibodies, and analyzed by flow cytometry. Plasma cells (PC) were identified with antibodies against intracellular kappa light chain. We monitored nephritis severity by measuring proteinuria (Uristix) and analyzing pathological changes in kidney histology.  Serum auto-antibody levels (anti-dsDNA) were measured by ELISA. ELISpot was used to enumerate IgG- and dsDNA antibody secreting cells (ASC). 

Results:  KPT-251 SINE treatment of NZB/W F1 mice prevented nephritis progression with a statistically significant reduction in urine protein levels in the treated group (p<0.05 beginning at 3 weeks) and notably reduced the number of mice with significant proteinuria (77% of treated mice had low urine protein concentrations <100 mg/dL compared to only 10% of controls at 5 weeks) (p=0.003). Importantly, serum anti-dsDNA IgG levels were significantly reduced after KPT-251 treatment (>6-fold reduction, p=0.0017) with profound effects on antibody secreting plasma cells. We found a significant reduction in splenic plasmablasts (2.18-fold reduction, p=0.001), BM PCs (2-fold reduction, p=0.02) and plasmablasts (MHCII high) (2.24-fold reduction, p=0.003).  Moreover, ASC numbers were notably decreased with nuclear transport inhibition.  Total IgG and anti-dsDNA IgG ASC numbers in the spleen were drastically reduced after treatment  (70% reduction, p=0.002).  In bone marrow, there was a pronounced decline in IgG ASC numbers (81%), with a more dramatic effect on anti-dsDNA IgG ASCs (96% reduction, p=0.002). 

Conclusion: These results suggest that nuclear transport inhibition preferentially affects auto-reactive PC and prevents SLE-associated nephritis. Therefore, these data support the further development of SINE drugs as a novel therapeutic approach for SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-nuclear-export-inhibitors-deplete-autoreactive-plasma-cells-and-protect-mice-with-lupus-like-disease-from-nephritis/