title: Antibody response against perlecan and collagen types IV and VI in chronic renal allograft rejection in the rat.
abstract: Chronic rejection is the leading cause of late renal transplant failure. Various structural lesions are observed in grafts undergoing chronic rejection including glomerular basement membrane (GBM) duplications. The well-established Fisher (F344) to Lewis (LEW) rat renal transplant model for chronic rejection was used to assess the presence and role of the humoral immune response against graft antigens during chronic rejection. LEW recipients of F344 allografts develop transplant glomerulopathy and produce IgG1 antibodies directed against F344 GBM preparations that are detectable 3 weeks after transplantation. Glomerular IgG1 deposition was observed that in vitro co-localized with a rabbit anti-rat GBM antiserum in rejecting F344 grafts; elution experiments of isolated glomeruli yielded IgG1 antibodies reactive in vitro with F344 GBM, but not LEW GBM. Prevention of acute rejection by transient treatment of the recipients with cyclosporin A completely abrogated the production of anti-GBM antibodies. Using proteomic techniques we identified the antigens recognized by the LEW posttransplant sera as being the heparan sulfate proteoglycan perlecan and the alpha1 chain of collagen type VI in association with the alpha5 chain of collagen type IV. In conclusion, LEW recipients of F344 kidney grafts produce IgG1 antibodies against donor type perlecan and alpha1(VI)/alpha5(IV) collagen and develop transplant glomerulopathy. These data implicate an important role for the humoral immune response in the development of glomerulopathy during chronic rejection.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands. s.a.joosten@lumc.nl
authors.forename: Simone A
authors.initials: SA
authors.lastname: Joosten
authors.forename: Mieneke G A
authors.initials: MG
authors.lastname: van Dixhoorn
authors.forename: Maria C
authors.initials: MC
authors.lastname: Borrias
authors.forename: Hallgrimur
authors.initials: H
authors.lastname: Benediktsson
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.forename: Leendert C
authors.initials: LC
authors.lastname: Paul
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology; D015153:Blotting, Western; D002908:Chronic Disease; D024141:Collagen Type IV / Q000276:immunology*; D024142:Collagen Type VI / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology*; D007074:Immunoglobulin G / Q000032:analysis / Q000276:immunology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D024141:Collagen Type IV; D024142:Collagen Type VI; D019812:Heparan Sulfate Proteoglycans; D007074:Immunoglobulin G; C071927:perlecan