Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production, immune complex deposition and multisystem involvement.  Calcium/calmodulin-dependent protein kinase type IV (CaMK4) is serine-threonine kinase overexpressed in SLE CD4 T cells. Global CaMK4 deficiency or inhibition with a small drug in MRL/lpr mice resulted in prolonged survival, significant suppression of proteinuria, severity of glomerulonephritis and autoantibody production. Here, we hypothesized that targeted T cell specific deletion of CaMK4 will protect mice from the development of systemic autoimmune disease induced by application of imiquimod, a toll-like receptor agonist.

Methods: We generated T cell specific CaMK4 conditionally deficient mice on C57BL/6 background by using Cre-loxP system.  Mice harboring loxP sites of Camk4 gene  ( Camk4 ^flox/flox) were crossed with Cre transgenic mice driven by distal Lck promoter.  Female mice were genotyped and 12 weeks old Lck-Cre positive and negative Camk4 ^flox/flox littermates  were used for the experiment. Mice were treated with imiquimod applied to the ears 3 times weekly for 8 weeks.  Serum, urine, kidneys and other organs were collected for the analysis. Levels of dsDNA were measured by ELISA.  Proteinuria was assessed by measuring albumin to creatinine ratio. Kidney sections were scored for damage in a blinded manner by using the renal activity index. T- test was used for statistical analysis and data are expressed as mean±SEM.

Results: Lck-Cre+ Camk4 ^flox/flox mice had normal development and lifespan.  We had 4 Lck-Cre Camk4 ^flox/flox negative and positive mice per group.  After 8 weeks of imiquimod treatment elevated levels of autoantibodies to double-stranded DNA were similar between the groups  ( Lck-Cre +/ Camk4 ^flox/flox :18.68±1.72 vs. Lck-Cre -/ Camk4 ^flox/flox 21.73± 3.34 IU /ml).  Spleen sizes were similar between the groups.  Excitingly, proteinuria was significantly decreased in Lck-Cre +/ Camk4 ^flox/flox mice compared to Lck-Cre negative (871.94±227.24 vs. 1437.9±275.56 mg/gr; p= 0.0023).  Histopathologic examination of the kidneys showed  that T cell specific CaMK4 deficiency in LcK-Cre positive animals significantly decreased infiltration in the kidney parenchima.

Conclusion: We have generated evidence that specific deletion of CaMKIV in T cells ameliorates severity of glomerulonephritis after the administration of the TLR7 agonist without affecting the production of antibodies to dsDNA. Our data support the development targeted delivery of a CaMK4 inhibitors to T cells for the treatment of patients with SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/t-cell-specific-camkiv-deficiency-protects-mice-from-imiquimod-induced-glomerulonephritis/