Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis.
The CCL2/CCR2 chemokine/receptor axis directs the chemotaxis of infiltrating monocytes/macrophages and T cells and plays a pivotal role in tissue damage and fibrosis in kidney diseases. The eradication of the activated leucocytes should diminish the production of inflammatory mediators, limit tissue damage and ameliorate disease. A recombinant fusion protein (OPL-CCL2-LPM) comprised of the human CCL2 (monocyte chemoattractant protein-1) chemokine fused to a truncated form of the enzymatically active A1 domain of Shigella dysenteriae holotoxin (SA1) has been developed. The CCL2 portion binds specifically to CCR2-bearing leucocytes and the fusion protein enters the cells, where the SA1 moiety inhibits protein synthesis resulting in cell death. The compound was tested in a model of anti-thymocyte serum (ATS)-induced mesangioproliferative glomerulonephritis (ATS-GN). Male rats were injected with ATS on day 0 and treated intravenously with vehicle, 50 or 100 microg/kg of OPL-CCL2-LPM Q2D from days 2, 4, 6 and 8. Urine and blood were collected on days 0, 5 and 9. Animals were sacrificed on day 9. No treatment-related effects on body weight or signs of clinical toxicity were observed. Urine protein levels were decreased in treated animals. At the highest dose, histopathological analyses of kidney sections revealed maximum reductions of 36, 31, 30 and 24% for macrophage count, glomerular lesions, alpha-smooth muscle actin and fibronectin respectively. These results indicate a significant protective effect of OPL-CCL2-LPM in this model of nephritis.
McIntosh
L M
LM
Osprey Pharmaceuticals Limited, St Laurent, Quebec, Canada.
Barnes
J L
JL
Barnes
V L
VL
McDonald
J R
JR
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D002634:Chemotaxis, Leukocyte; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008262:Macrophage Activation; D008297:Male; D009000:Monocytes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D022621:Shiga Toxin / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014407:Tumor Cells, Cultured
C111835:CCL2 protein, human; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D011993:Recombinant Fusion Proteins; D022621:Shiga Toxin