Background Autoimmune diseases such as systemic lupus erythematosus (SLE) display quantitative (1) and/or qualitative (2) deficiencies of Foxp3⁺ regulatory T (T_reg) cells and this is considered to contribute to immune dysregulation and organ damage (3). Calcium/calmodulin-dependent protein kinase IV (CaMK4) is expressed at increased levels in T cells from SLE patients (4) and lupus-prone mice (5).

Objectives T_reg are pivotal for the maintenance of peripheral tolerance and prevent development of autoimmune diseases. We have reported that CaMK4 deficient MRL/lpr mice display less disease activity by promoting IL-2 production and increasing the activity of T_reg cells. To further define the mechanism of CaMK4 on T_reg cells in SLE, we used the Foxp3-GFP reporter mice and treated them with KN-93, an inhibitor of CaMK4.

Methods We generated MRL/lpr Foxp3-GFP mice to record T_reg cells; stimulated naïve CD4⁺ T cells from MRL/lpr Foxp3-GFP mice under T_reg polarizing conditions in the absence or presence of KN-93; evaluated the number of GFP` positive cells in lymphoid organs and examined skin and kidney pathology at 16 week of age. We also examined the infiltration of cells and recruitment of T_reg cells in the kidney.

Results We show that culture of MRL/lpr Foxp3-GFP T cells in the presence of KN-93 promotes T_reg differentiation in a dose dependent manner (Fig. F). Treatment of MRL/lpr Foxp3-GFP mice with KN-93 results in significant induction of T_reg cells in the spleen, peripheral lymph nodes (Fig. B-E) and peripheral blood (Fig. A and B) and this is accompanied by decreased skin and kidney damage. Notably, KN-93 clearly diminishes the accumulation of inflammatory cells along with reciprocally increased T_reg cells in target organ.

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Figure 1

Conclusions Our results indicate that KN-93 treatment enhances the generation of T_reg cells in vitro and in vivo highlighting its potential therapeutic use for the treatment of human autoimmune diseases.

References

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2. Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S. Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum. 2008;58(3):801-12.

3. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636-45.

4. Juang YT, Wang Y, Solomou EE, Li Y, Mawrin C, Tenbrock K, et al. Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV. J Clin Invest. 2005;115(4):996-1005.

5. Koga T, Ichinose K, Mizui M, Crispin JC, Tsokos GC. Calcium/Calmodulin-Dependent Protein Kinase IV Suppresses IL-2 Production and Regulatory T Cell Activity in Lupus. J Immunol. 2012;189(7):3490-6.

Acknowledgements This work was supported by NIH grants RO1 AI R01AI085567 and AR064350.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.2491