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 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.
Footnotes
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This work was supported by NOXXON PharmaAG.
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Parts of this project were prepared as a doctoral thesis: Kulkarni O (2008) Therapeutic MCP-1 blockade in murine Lupus nephritis. Ph.D. thesis, University of Munich, Munich, Germany.
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The other authors have no conflict of financial interest.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.142711.
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ABBREVIATIONS: DPLN, diffuse proliferative lupus nephritis; CYC, cyclophosphamide; MMF, mycophenolate mofetil; SLE, systemic lupus erythematosus; IL, interleukin; TNF, tumor necrosis factor; ELISA, enzyme-linked immunosorbent assay; CFU, colony-forming unit; GM, granulocyte macrophage.
- Received June 26, 2008.
- Accepted November 6, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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