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 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-alpha 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 7/4(high) 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.

• Authors: Onkar Kulkarni, Dirk Eulberg, Norma Selve, Stefan Zöllner, Ramanjaneyulu Allam, Rahul D Pawar, Stephanie Pfeiffer, Stephan Segerer, Sven Klussmann, Hans-Joachim Anders
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 2 Pg. 371-7 (Feb 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 18997060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aptamers, Nucleotide
• Chemokine CCL2
• Immunosuppressive Agents
• NOX-E36-3'PEG, mouse
• Cyclophosphamide

Topics

• Animals
• Aptamers, Nucleotide (pharmacokinetics, therapeutic use)
• Chemokine CCL2 (antagonists & inhibitors, immunology)
• Cyclophosphamide (administration & dosage, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Synergism
• Female
• Immunosuppressive Agents (pharmacokinetics, therapeutic use)
• Kidney (drug effects, pathology)
• Lupus Nephritis (drug therapy, metabolism)
• Mice
• Mice, Inbred MRL lpr
• Pneumonia (drug therapy, metabolism)
• T-Lymphocytes (drug effects, immunology)