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Abstract Number: 663

STAT3 Inhibition Delays the Onset of Lupus Nephritis in MRL/Lpr Mice

Linsday Edwards1 and Vasileios C. Kyttaris2, 1Medicine/Rheumatology, Beth Israel Deaconess Medical Center, Boston, MA, 2Medicine/Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Lupus, T cells and transcriptional regulation

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Session Information

Session Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose

The transcription factor Signal transducer and activator of transcription (STAT) 3 is overexpressed and aberrantly activated in patients with SLE as well as lupus-prone mice. More specifically, STAT3 plays a central role in T cell differentiation into pathogenic Th17 as well as T follicular helper cells, two T cell subsets that are thought to orchestrate autoimmune responses in SLE. Our previous studies have shown that STAT3 is also important in SLE T cell migration in response to chemokines. To better understand its role in SLE, we inhibited STAT3 in lupus-prone mice using the small molecule Stattic. 

Methods

MRL/lpr mice were treated 3 times per week with 10 mg/kg of the STAT3 inhibitor Stattic or vehicle delivered intraperitoneally beginning at 6 weeks of age and continuing through 15 weeks of age. The kidney function was monitored weekly by urinalysis. Levels of anti-dsDNA antibodies, C3 and various cytokines were measured in the serum. At the conclusion of treatment, tissues were harvested for histology and phenotypic analysis. In vitro assessment of the effects of Stattic treatment on T cell function was also performed. 

Results

Stattic treated mice exhibited a delay in the onset of proteinuria by approximately 3 weeks. Stattic treated mice had lower levels of anti-dsDNA production (mean=1771 U/ml in treated vs. 32174 U/ml in control) and inflammatory cytokine production (serum IL-17 levels approximately 2-fold higher in untreated mice). Inhibitor treatment reduced lymphadenopathy, and resulted in a decrease in the total number of T cells in treated mice. Absolute numbers of T cells were 3-4 fold higher in untreated mice. Furthermore, the numbers of T follicular helper cells were reduced in Stattic treated mice by 4-fold. Complimentary in vitro experiments showed that T cells treated with Stattic exhibited a dose dependent decrease in proliferation and an approximately 70% decrease in their ability to migrate in response to CXCL12 stimulation. 

Conclusion

From the data generated in this study, we conclude that treatment of lupus prone mice with a STAT3 inhibitor delays the onset of autoimmunity and end-kidney damage. Our in vivo and in vitro findings suggest that STAT3 inhibition leads to the following: a. decreased T cell proliferation, b. decreased Tfh cells and decreased anti-dsDNA production, and c. decreased cell migration in response to chemokines. We propose that STAT3 inhibition represents a therapeutic target in SLE and in particular lupus nephritis.


Disclosure:

L. Edwards,
None;

V. C. Kyttaris,
None.

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