Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice.

The monocyte chemoattractant protein CCL2 is crucial for monocyte and T cell recruitment from the vascular to the extravascular compartment at sites of inflammation. CCL2 is expressed in human lupus nephritis and was shown to mediate experimental lupus; therefore, CCL2 antagonists may be beneficial for therapy. This study describes the l-enantiomeric RNA oligonucleotide mNOX-E36, a so-called Spiegelmer that binds murine CCL2 with high affinity and neutralizes its action in vitro and in vivo. The mirror image configuration of the Spiegelmer confers nuclease resistance and thus excellent biostability. mNOX-E36 does not induce type I IFN via Toll-like receptor-7 or cytosolic RNA receptors, as recently shown for certain synthetic D-RNA. Autoimmune-prone MRL(lpr/lpr) mice that were treated with a polyethylene glycol form of mNOX-E36 from weeks 14 to 24 of age showed prolonged survival associated with a robust improvement of lupus nephritis, peribronchial inflammation, and lupus-like inflammatory skin lesions. Thus, mNOX-E36-based inhibition of CCL2 represents a novel strategy for the treatment of autoimmune tissue injury, such as lupus nephritis.

[1]  Gunther Hartmann,et al.  5'-Triphosphate RNA Is the Ligand for RIG-I , 2006, Science.

[2]  V. Pascual,et al.  Type I interferon in systemic lupus erythematosus and other autoimmune diseases. , 2006, Immunity.

[3]  K. Messlinger,et al.  Inhibition of stimulated meningeal blood flow by a calcitonin gene‐related peptide binding mirror‐image RNA oligonucleotide , 2006, British journal of pharmacology.

[4]  K. Ishii,et al.  Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses , 2006, Nature.

[5]  C. Selmi,et al.  Interferon alpha and its contribution to autoimmunity. , 2006, Current opinion in investigational drugs.

[6]  S. Klußmann,et al.  An L-RNA-based aquaretic agent that inhibits vasopressin in vivo. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Pamer,et al.  Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2 , 2006, Nature Immunology.

[8]  R. Alon,et al.  Immune cell migration in inflammation: present and future therapeutic targets , 2005, Nature Immunology.

[9]  D. Busch,et al.  Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. , 2005, Journal of the American Society of Nephrology : JASN.

[10]  M. Kretzler,et al.  Toll-like receptor-7 modulates immune complex glomerulonephritis. , 2005, Journal of the American Society of Nephrology : JASN.

[11]  S. Akira,et al.  Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7 , 2005, Nature Medicine.

[12]  M. Tschöp,et al.  Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  K. Masutani,et al.  Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice. , 2004, Rheumatology.

[14]  L. Steinman.  Immune Therapy for Autoimmune Diseases , 2004, Science.

[15]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[16]  J. Miyazaki,et al.  Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. , 2003, Arthritis and rheumatism.

[17]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..

[18]  S. Klußmann,et al.  In vivo properties of an anti-GnRH Spiegelmer: An example of an oligonucleotide-based therapeutic substance class , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Cohen,et al.  A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation. , 2002, The Journal of clinical investigation.

[20]  H. Maier,et al.  Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis. , 2001, Journal of the American Society of Nephrology : JASN.

[21]  B. Rollins,et al.  Chemokines and disease , 2001, Nature Immunology.

[22]  Joyce Nelson,et al.  Pharmacokinetics and Safety of an Anti-Vascular Endothelial Growth Factor Aptamer (NX1838) Following Injection into the Vitreous Humor of Rhesus Monkeys , 2000, Pharmaceutical Research.

[23]  B. Rollins,et al.  Monocyte Chemoattractant Protein 1–Dependent Leukocytic Infiltrates Are Responsible for Autoimmune Disease in Mrl-Faslpr Mice , 1999, The Journal of experimental medicine.

[24]  M. Baggiolini.  Chemokines and leukocyte traffic , 1998, Nature.

[25]  V. Erdmann,et al.  Mirror-image RNA that binds D-adenosine , 1996, Nature Biotechnology.

[26]  J. Szostak,et al.  In vitro selection of RNA molecules that bind specific ligands , 1990, Nature.

[27]  L. Gold,et al.  Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. , 1990, Science.

[28]  L R Muenz,et al.  Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. , 1984, Kidney international.

[29]  P. Galle,et al.  Interferon-beta: a therapeutic for autoimmune lupus in MRL-Faslpr mice. , 2005, Journal of the American Society of Nephrology : JASN.

[30]  P. Galle,et al.  Interferon- (cid:1) : A Therapeutic for Autoimmune Lupus in MRL- Fas lpr Mice , 2022 .