Development of a novel Poly (I:C)-induced murine model with accelerated lupus nephritis and examination of the therapeutic effects of mycophenolate mofetil and a cathepsin S inhibitor.

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multi-organ systems with a widely heterogeneous clinical presentation. Renal involvement, observed mainly in lupus nephritis (LN), is the most common organ lesion associated with SLE and a determinant of prognosis. However, treatment of LN remains controversial and challenging, prompting the need for novel therapeutic approaches. In particular, development of a clinically relevant LN animal model would greatly facilitate the development of new treatments. Here, we report a novel murine model for LN established by administering polyinosinic-polycytidylic acid (Poly (IC)) to NZB/W F1 mice. We investigated the effectiveness of administering Poly (IC) to NZB/W F1 mice for accelerating nephritis onset and explored the optimal conditions under which to enroll mice with nephritis with similar pathology for studying treatment candidates. Gene-expression analysis revealed that activation of macrophages, which are reported to be involved in the progression of LN in patients, was a unique characteristic in this accelerated nephritis model. Evaluation of the therapeutic effect of mycophenolate mofetil (MMF), a recommended first-choice agent for LN, in this novel LN model showed that MMF significantly reduced proteinuria. The cathepsin S (CatS) inhibitor ASP1617, which has been reported to prevent development of lupus-like glomerulonephritis in the spontaneous NZB/W F1 mouse model, also showed marked therapeutic effect in this model. Our novel Poly (IC) accelerated LN model would thus be very useful for screening clinical candidates for LN, and CatS may be an attractive therapeutic target for the treatment of LN.