PT  - JOURNAL ARTICLE
AU  - Kulkarni, Onkar
AU  - Eulberg, Dirk
AU  - Selve, Norma
AU  - Zöllner, Stefan
AU  - Allam, Ramanjaneyulu
AU  - Pawar, Rahul D.
AU  - Pfeiffer, Stephanie
AU  - Segerer, Stephan
AU  - Klussmann, Sven
AU  - Anders, Hans-Joachim
TI  - Anti-Ccl2 Spiegelmer Permits 75% Dose Reduction of Cyclophosphamide to Control Diffuse Proliferative Lupus Nephritis and Pneumonitis in MRL-Fas(lpr) Mice
AID  - 10.1124/jpet.108.142711
DP  - 2009 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 371--377
VI  - 328
IP  - 2
4099  - http://jpet.aspetjournals.org/content/328/2/371.short
4100  - http://jpet.aspetjournals.org/content/328/2/371.full
SO  - J Pharmacol Exp Ther2009 Feb 01; 328
AB  - 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 MRLlpr/lpr mice with DPLN from 14 weeks of age with vehicle, weekly 30 mg/kg CYC (full dose), monthly 30 mg/kg CYC (one-fourth full dose), pegylated control Spiegelmer, pegylated anti-Ccl2 Spiegelmer (3/week), pegylated anti-Ccl2 Spiegelmer plus CYC one-fourth full dose and mycophenolate mofetil. At week 24, DPLN and autoimmune lung injury were virtually abolished with CYC full dose but not with CYC one-fourth full dose. The CYC one-fourth full dose/Spiegelmer combination was equipotent to CYC full dose on kidney and lung injury. CD3+CD4-CD8- and CD3+CD4+CD25+ T cells and serum interleukin-12p40 and tumor necrosis factor-α levels were all markedly affected by CYC full dose but not by CYC one-fourth full dose. No additive effects of anti-Ccl2 Spiegelmer were noted on bone marrow colony-forming unit-granulocyte macrophage counts and 7/4high monocyte counts, lymphoproliferation, and spleen T cell depletion. In summary, anti-Ccl2 Spiegelmer permits 75% dose reduction of CYC for controlling 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 a novel strategy to reduce CYC toxicity in the treatment of severe lupus. The American Society for Pharmacology and Experimental Therapeutics