Inhibiting Tyrosine Kinase 2 Ameliorates Antiphospholipid Syndrome Nephropathy.

Abstract

Antiphospholipid antibody syndrome (APS) is an autoimmune disease characterized by the presence of2-glycoprotein I (2-GPI)-targeting antiphospholipid antibodies (aPLs) and vascular thrombosis or obstetrical complications. One of its severe manifestations is nephropathy.To examine the role of type I interferon (IFN) and therapeutic potential of tyrosine kinase 2 (Tyk2) inhibition, we administered BMS-986202, a novel Tyk2 inhibitor, in a mouse model of APS nephropathy. We administered BMS-986202 to BALB/c mice at a dose of 2 mg/kg. Biochemical and histological characteristics of APS nephropathy were then determined. The type I IFN signature in the kidney was also evaluated by real-time polymerase chain reaction (PCR).The Tyk2 inhibitor reversed the elevation of blood urea nitrogen (BUN) and microalbuminuria in the murine model of APS nephropathy. In addition, the Tyk2 inhibitor reversed the pathological vascular changes in the kidney as judged in electron microscopy (EM), and fibrin and C3 deposition as revealed in immunohistochemistry (IHC). An increased expression levels of IFN signature (IFN regulatory factor 7 (IRF7) and Mx1) in the kidneys of APS mice were found. Tyk2 inhibition reversed such an upregulation.Our results demonstrated the key role of type I IFN in the pathogenesis of APS nephropathy. Furthermore, the therapeutic efficacy of Tyk2 inhibition was demonstrated in a murine model of APS nephropathy. Our results could provide a new treatment strategy for this debilitating disease.