Received for publication June 26, 2008.
Revised November 6, 2008.
Accepted for publication November 6, 2008.

Anti-Ccl2 Spiegelmer permits 75% dose reduction of cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice

Abstract

Cyclophosphamide (CYC) can control diffuse proliferative lupus nephritis (DPLN) by potent immunosuppression but remains associated with serious and life threatening complications. Drugs that specifically target mediators of DPLN may help to reduce CYC dose and side effects. Monocyte chemoattractant protein MCP-1/CCL2 mediates monocyte and T cell recruitment in DPLN and Ccl2-specific L-enantiomeric RNA Spiegelmer mNOX-E36 neutralizes the biological effects of murine Ccl2 in-vitro and in-vivo. We injected MRL^lpr/lpr mice with DPLN from 14 weeks of age with either vehicle, weekly 30 mg/kg CYC (full dose), monthly 30 mg/kg CYC ( full dose), pegylated control Spiegelmer, pegylated anti-Ccl2 Spiegelmer (3/week), pegylated anti-Ccl2 Spiegelmer plus CYC full dose and mycophenolate mofetil (MMF). At week 24, DPLN and autoimmune lung injury were virtually abolished with CYC full dose but not with CYC full dose. The CYC full dose/Spiegelmer combination was equipotent to CYC full dose on kidney and lung injury. CD3⁺CD4^-CD8^- and CD3⁺CD4⁺CD25⁺ T cells, serum IL-12p40 and TNF- levels which were all markedly affected by CYC full dose but not by CYC full dose. No additive effects of anti-Ccl2 Spiegelmer were noted on bone marrow CFU-GM counts and 7/4 ^high monocyte counts, lymphoproliferation, spleen T cell depletion. In summary, anti-Ccl2 Spiegelmer permits 75% dose reduction of CYC for controling DPLN and pneumonitis in MRL-Fas(lpr) mice, sparing suppressive effects of full dose CYC on myelosuppression and T cell depletion. We propose anti-Ccl2 Spiegelmer therapy as novel strategy to reduce CYC toxicity in the treatment of severe lupus

Key words: MCP-1, autoimmune disease, chemokines, lupus nephritis, myelosuppression, pharmacotherapy