A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis

PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF betabeta-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist. Low levels of PDGF-...

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Published in:	Journal of the American Society of Nephrology Vol. 14; no. 9; pp. 2237 - 2247
Main Authors:	OSTENDORF, Tammo, VAN ROEYEN, Claudia R. C, KEYT, Bruce A, LICHENSTEIN, Henri S, LAROCHELLE, William J, FLOEGE, Jürgen, PETERSON, Jeffrey D, KUNTER, Uta, EITNER, Frank, HAMAD, Avin J, CHAN, Gerlinde, JIA, Xiao-Chi, MACALUSO, Jennifer, GAZIT-BORNSTEIN, Gadi
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 01-09-2003
Subjects:	Animals Antibodies, Monoclonal - immunology Biological and medical sciences Cell Division - physiology Cells, Cultured Down-Regulation Glomerular Mesangium - metabolism Glomerulonephritis Glomerulonephritis, Membranoproliferative - immunology Glomerulonephritis, Membranoproliferative - metabolism Humans Lymphokines Medical sciences Mice Nephrology. Urinary tract diseases Nephropathies. Renovascular diseases. Renal failure Platelet-Derived Growth Factor - immunology Platelet-Derived Growth Factor - metabolism Rats Up-Regulation Kidney disease Human In vivo Urinary system disease Pathogenesis Mediator Monoclonal antibody Mesangial proliferative glomerulonephritis
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Summary:	PDGF-B is of central importance in mesangioproliferative diseases. PDGF-D, a new PDGF isoform, like PDGF-B, signals through the PDGF betabeta-receptor. The present study first determined that PDGF-D is mitogenic for rat mesangial cells and is not inhibited by a PDGF-B antagonist. Low levels of PDGF-D mRNA were detected in normal rat glomeruli. After induction of mesangioproliferative nephritis in rats by anti-Thy 1.1 mAb, glomerular PDGF-D mRNA and protein expression increased significantly from days 4 to 9 in comparison with nonnephritic rats. Peak expression of PDGF-D mRNA occurred 2 d later than peak PDGF-B mRNA expression. In addition, PDGF-D serum levels increased significantly in the nephritic animals on day 7. For investigating the functional role of PDGF-D, neutralizing fully human mAb were generated using the XenoMouse technology. Rats with anti-Thy 1.1-induced nephritis were treated on days 3 and 5 with different amounts of a fully human PDGF-DD-specific neutralizing mAb (CR002), equal amounts of irrelevant control mAb, or PBS by intraperitoneal injection. Specific antagonism of PDGF-D led to a dose-dependent (up to 67%) reduction of glomerular cell proliferation. As judged by double immunostaining for 5-bromo-2'-deoxyuridine and alpha-smooth muscle actin, glomerular mesangial cell proliferation was reduced by up to 57%. Reduction of glomerular cell proliferation in the rats that received CR002 was not associated with reduced glomerular expression of PDGF-B mRNA. PDGF-D antagonism also led to reduced glomerular infiltration of monocytes/macrophages (day 5) and reduced accumulation of fibronectin (day 8). In contrast, no effect was noted in normal rats that received an injection of CR002. These data show that PDGF-D is overexpressed in mesangioproliferative states and can act as an auto-, para-, or even endocrine glomerular cell mitogen, indicating that antagonism of PDGF-D may represent a novel therapeutic approach to mesangioproliferative glomerulonephritides.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1046-6673 1533-3450
DOI:	10.1097/01.asn.0000083393.00959.02