Session Title: Plenary Session III: Discovery 2012
Session Type: Plenary Sessions
Background/Purpose: Lupus nephritis (LN) depends on autoAb deposition and activation of multiple cell types that infiltrate kidneys and promote inflammation – monocytes/macrophages (MM), DCs, T and B cells. Laquinimod (LAQ) administered to humans downregulates Ag presentation, decreases chemokine production, decreases MHC expression on MM, and induces apoptotic pathways in PBMC (Gurevich M et al 2010). LAQ reduces progression of relapsing remitting multiple sclerosis (Comi G et al NEJM 2012); it is currently in clinical trials in SLE. MMF targets primarily lymphocytes; it is effective in many LN patients
Methods: We compared clinical and immune cell changes in groups of 10-12 BWF1 female mice treated orally 3 times a week for 24 weeks with a) water; b) LAQ 1 mg/kg; c) LAQ 25 mg/kg; d) MMF 30 mg/kg; e) MMF100 mg/kg.
Results: Survival was better in both LAQ groups and the MMF100 group vs controls (p=0.028). LAQ at both doses was equivalent to MMF100 in preventing proteinuria in mice treated before disease appeared. At 32 wks of age 50% of mice on water had proteinuria vs zero in LAQ and MMF100 groups (p<0.0001) Renal histology mirrored proteinuria: mean total histologic scores were 7.8 on water, 1.0 on LAQ and 0.9 on MMF100 (p<0.01 both treatment groups compared to controls). Glomerular deposition of Ig and C3 were in the normal range in LAQ and MMF, but significantly increased in the water group (p<0.001).
Mice treated after clinical nephritis appeared (≥3+ proteinuria) improved on LAQ: after 3 wks of treatment proteinuria was present in 100% on water vs 25% on LAQ (p<0.001). Survival was also better in mice treated with LAQ (p<0.0001)
Effects on splenic PBMC differed between LAQ and MMF. Neither treatment changed total numbers of B cells. MMF decreased CD4+and CD8+ T cell percents; LAQ did not. LAQ compared to MMF increased numbers of two putative regulatory cells, CD4+CD25+Foxp3+ Treg and CD11b+Ly6intGR-1+ myeloid MM. Most interesting was the observation that LAQ, but not MMF, significantly reduced numbers of MM.
Conclusion: LAQ was highly effective in preventing and suppressing proteinuria and glomerular immune disease in BWF1 mice. Responses to MMF in high dose were similarly good. However, LAQ reduced numbers of MM, and MMF did not. In addition, LAQ induced different types of regulatory cells, distinguishing it from MMF. Since suppression of MM is likely to reduce renal inflammation and damage, future development of LAQ as a therapeutic for lupus nephritis is especially promising.
B. H. Hahn,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/laquinimod-laq-is-equivalent-to-mycophenolate-mofetil-mmf-in-preventing-and-suppressing-murine-lupus-nephritis-and-has-greater-effects-on-myeloidmonocytemacrophage-cells/