THU0375 Inhibition of Stat3 Alleviates Nephritis in Lupus Prone Mice
Authors: V. Kyttaris
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Previous data have shown that the transcription factor Signal transducer and activator of transcription (STAT) 3 is increased in patients with SLE and is directly responsible for aberrant in vitro T cell migration (1). Moreover 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 (2). <h3>Objectives</h3> To better understand the role of STAT3 in SLE, we used the small molecule Stattic to inhibit its activation in lupus prone MRL/lpr mice. <h3>Methods</h3> MRL/<i>lpr</i> 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. <i>In vitro</i> assessment of the effects of Stattic treatment on T cell function was also performed. <h3>Results</h3> 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 <i>in vitro</i> 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. <h3>Conclusions</h3> 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 <i>in vivo</i> and <i>in vitro</i> 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. <h3>References</h3> Harada T, Kyttaris VC, Li Y, Juang Y-T, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity 2007; 40(1): 1-8. Crispín JC, Kyttaris VC, Terhorst C, Tsokos GC. T cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010; 6(6): 317-25. <h3>Acknowledgements</h3> Masayuki Misui, Stacy Rivera and Linsday Edwards performed the in vitro experiments and helped with data analysis. <h3>Disclosure of Interest</h3> V. Kyttaris Grant/research support from: CSL/Behring, Bristol Myer Squibb