Background/Purpose: There is great interest in developing new treatment approaches for systemic lupus erythematosus (SLE), but the biologic therapies under investigation over the past several years have yielded variable results. Recently the nuclear export protein Exportin 1 (XPO1, also known as CRM1) has surfaced as an attractive target for the treatment of malignancies and autoimmune disorders. Selective Inhibitor of Nuclear Export (SINE) compounds are potent, orally available and well tolerated XPO1 inhibitors that have shown potent activity in human phase I/II clinical trials against various hematologic malignancies. SINE compounds exert apoptotic and anti-inflammatory effects by mediating nuclear retention of important XPO1 cargos like the NFκB pathway regulatory protein, IκB. Based on the central role of NFκB signaling in the activation of immune cells in SLE, we evaluated the therapeutic efficacy of SINE compounds in murine SLE.

Methods:

Cohorts of nephritic NZB/W F1 lupus-prone female mice, with established disease (elevated anti-dsDNA antibody titer and proteinuria) were treated with low or high dose KPT-350 (5 or 7.5 mg/kg, respectively) or a vehicle control three times per week for 8 weeks (n=8 per group). Proteinuria was monitored and kidney histology assessed. Spleen, bone marrow (BM), and kidney cells were harvested and analyzed by flow cytometry. Antibody secreting cells (ASCs) and germinal centers (GCs) were enumerated and measured by ELIspot and immunofluorescent staining. Serum samples and RNA were collected for Luminex assay and qPCR.

Results: Treatment with SINE compounds significantly prevented increases in proteinuria (proteinuria scores: Control: 2.12±1.12; SINE (5 mg/kg): 1.06± 0.49; SINE (7.5 mg/kg): 0.85±0.55) and drastically decreased IgG deposition and kidney pathology. Prevention of kidney damage was associated with a remarkable disruption of splenic GC, a significant reduction in the number of auto-reactive ASC, and a decrease in the accumulation of auto-reactive ASC in the inflamed kidney. Reduced numbers of plasma cells (PCs) in the inflamed kidney are likely due to the drastic decrease in the expression of molecules critical for PC attraction (CCL2, CXCL9, CXCL10, CXCL11) and survival (BAFF, APRIL). The potent effect of SINE compounds on GC and auto-reactive ASC is noticeable as early as 1 week after starting therapy. However, kinetics studies showed that a more pronounced elimination of GC and auto-reactive ASC is achieved after 8 weeks. Although SINE therapy has a drastic impact on spleen architecture, recovery experiments showed that complete recovery of immune cells in spleen occurred by 4 weeks. The reversible impact of SINE compounds on SLE provides a potential window of time for immunization of lupus patients.

Conclusion: SINE compounds have demonstrated efficacy in a murine model of SLE by reducing generation, survival and function of auto-reactive immune cells. It is likely that inhibition of the canonical NFκB pathway underlies KPT-350’s inhibitory effect. Together, our findings suggest the potential of SINE compounds to have a significant impact on disease progression in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibitors-of-nuclear-export-prevent-lupus-progression-by-targeting-germinal-center-formation-and-autoreactive-antibody-secreting-cells/