Anti-Ccl2 Spiegelmer permits 75% dose reduction of cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis in MRL-Fas(lpr) mice.
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.
Kulkarni
Onkar
O
Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
Eulberg
Dirk
D
Selve
Norma
N
Zöllner
Stefan
S
Allam
Ramanjaneyulu
R
Pawar
Rahul D
RD
Pfeiffer
Stephanie
S
Segerer
Stephan
S
Klussmann
Sven
S
Anders
Hans-Joachim
HJ
D000818:Animals; D052157:Aptamers, Nucleotide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D052157:Aptamers, Nucleotide; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; C528578:NOX-E36-3'PEG, mouse; D003520:Cyclophosphamide