title: A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis.
abstract: 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.
authors.affiliation: Division Nephrology, University of Aachen, Germany.
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Peterson
authors.forename: Uta
authors.initials: U
authors.lastname: Kunter
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.forename: Avin J
authors.initials: AJ
authors.lastname: Hamad
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Chan
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Jia
authors.forename: Jennifer
authors.initials: J
authors.lastname: Macaluso
authors.forename: Gadi
authors.initials: G
authors.lastname: Gazit-Bornstein
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Keyt
authors.forename: Henri S
authors.initials: HS
authors.lastname: Lichenstein
authors.forename: William J
authors.initials: WJ
authors.lastname: LaRochelle
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D005920:Glomerular Mesangium / Q000378:metabolism*; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008222:Lymphokines; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D008222:Lymphokines; C427493:PDGFD protein, human; C498951:Pdgfd protein, mouse; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor