Inhibition of Calcium/Calmodulin-Dependent Protein Kinase 4 Ameliorates Th17 Related Autoimmune Disorder

Tomohiro Koga¹, Christian Hedrich¹, Masayuki Mizui², Nobuya Yoshida³, Linda Lieberman⁴, José C. Crispin¹ and George C. Tsokos⁵, ¹Medicine/Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ²Division of Rheumatology, Department of Medicine,, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ³Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ⁴Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, ⁵Rheumatology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: animal models and systemic lupus erythematosus (SLE), T cells

Session Information

Title: Systemic Lupus Erythematosus - Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: IL-17-producing T helper (Th17) cells have been causally linked to tissue inflammation in several autoimmune diseases including lupus and multiple sclerosis. Blockade of Th17 action or differentiation could therefore represent a useful therapeutic strategy in these settings.

Methods: We immunized C57B/6 mice or Camk4 deficient C57B/6 (B6 Camk4^-/-) mice with MOG 35-55 emulsified in complete Freund’s adjuvant (CFA) containing Mycobacterium tuberculosis and evaluated the disease activity. MRL/lpr mice were treated with KN-93, an antagonist of calcium/calmodulin-dependent protein kinase IV (CaMK4), and examined IL-17 producing T cell in the spleen and lymph node in vivo and in vitro. We also tested the number of infiltrated T cell and IL-17 related genes in lungs and kidneys. Furthermore, We compared the methylation status in Il2 or Il17A promoter and the binding capacity of cAMP response element modulator (CREM)-α to these promoters in Camk4 sufficient or deficetnt conditions. To determine the relevance of our findings to human SLE, we analyzed the effect of CaMK4 inhibition on Th17 cells function in T cells from patients.

Results: Here, we show that KN-93 inhibits Th17 cell differentiation both in vivo and in vitro. The relevance of this is reflected by the fact that B6 Camk4^-/- mice suffer less experimental autoimmune encephalomyelitis (EAE) and MRL/lpr Camk4^-/- have decreased autoimmunity and organ damage. Treatment of MRL/lpr mice with KN-93 decreases Th17 cell differentiation, prevents double negative T cells from infiltrating lungs and kidneys, and protects against organ damage. In in vitro experiments, KN-93 diminishes IL-17 production and reciprocally improves IL-2 production by CD4 T cells cultured under Th17-polarizing conditions. These effects are mediated through the activity of CREM-α that controls epigenetic remodeling of the Il2 and Il17a loci. Analogously, silencing of CaMK4 in T cells from patients with SLE and healthy controls decreases the expression of IL17A upon stimulation in the presence of TGF-β and IL-6.

Conclusion:

Collectively, our results suggest that CaMK4 inhibition might be a promising therapeutic agent for autoimmune diseases mediated by Th17 cells.

Disclosure:

T. Koga,
None;

C. Hedrich,
None;

M. Mizui,
None;

N. Yoshida,
None;

L. Lieberman,
None;

J. C. Crispin,
None;

G. C. Tsokos,
None.

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-calciumcalmodulin-dependent-protein-kinase-4-ameliorates-th17-related-autoimmune-disorder/