Article Text

PDF
THU0057 Kn-93, an Inhibitor of Calcium/Calmodulin-Dependent Protein Kinase Iv, Promotes Generation and Function of Foxp3+ Regulatory T Cells in Mrl/Lpr Mice
  1. T. Koga1,2,
  2. M. Mizui2,
  3. N. Yoshida2,
  4. K. Otomo2,
  5. L.A. Lieberman2,
  6. J.C. Crispín2,
  7. A. Kawakami1,
  8. G.C. Tsokos2
  1. 1Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University, Nagasaki, Japan
  2. 2Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Abstract

Background Autoimmune diseases such as systemic lupus erythematosus (SLE) display quantitative (1) and/or qualitative (2) deficiencies of Foxp3+ regulatory T (Treg) 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 Treg 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 Treg cells. To further define the mechanism of CaMK4 on Treg 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 Treg cells; stimulated naïve CD4+ T cells from MRL/lpr Foxp3-GFP mice under Treg 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 Treg cells in the kidney.

Results We show that culture of MRL/lpr Foxp3-GFP T cells in the presence of KN-93 promotes Treg differentiation in a dose dependent manner (Fig. F). Treatment of MRL/lpr Foxp3-GFP mice with KN-93 results in significant induction of Treg 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 Treg cells in target organ.

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

References

  1. Valencia X, Yarboro C, Illei G, Lipsky PE. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007;178(4):2579-88.

  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

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.