title: Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with alpha3 chain of type IV collagen.
abstract: BACKGROUND
  Glomerulonephritis and lung hemorrhage of autoimmune Goodpasture syndrome develop due to immune reactions against epitope(s) of the non-collagenous (NC1) domain of alpha3-chain of type IV collagen [alpha3(IV) NC1]. Whether thymic mechanisms have a role in the loss of tolerance to the Goodpasture epitope has not been established. We studied the renal and pulmonary effects of immunization with different forms (monomer, dimer, or hexamer) of alpha3(IV) NC1 collagen in Wistar-Kyoto (WKY) rats, and assessed whether the intrathymic inoculation of the antigen may protect against anti-GBM disease.
  
  
  METHODS
  WKY rats were immunized with bovine alpha3(IV) monomer, dimer, or hexamer, or with alpha3(IV) NC1 synthetic peptide. Renal function, kidney and lung immunohistology, and circulating and tissue bound antibodies to type IV collagen chains were analyzed. Effects of intrathymic inoculation of antigen on subsequent disease induction were analyzed in WKY rats given alpha3(IV) NC1 dimer or GBM preparation intrathymically 48 hours before immunization.
  
  
  RESULTS
  Proteinuria, linear IgG deposition in GBM, and crescentic glomerulonephritis developed in WKY rats immunized with alpha3(IV) NC1 dimer or hexamer. Lesions were dose-dependent upon injections of 10 to 100 microgram dimer. The alpha3(IV) NC1 monomer induced less severe proteinuria and no crescents. Pulmonary hemorrhage was detectable in 35% of rats immunized with 25 to 100 microgram alpha3(IV) NC1 dimer; alpha3(IV) synthetic peptide (36 carboxyl terminal) did not induce disease. Rats injected intrathymically with up to 100 microgram alpha3(IV) NC1 dimer or with GBM 48 hours before immunization were not protected against subsequent development of proteinuria and glomerulonephritis.
  
  
  CONCLUSIONS
  These findings document that glomerulonephritis and lung hemorrhage can be elicited in WKY rats by immunization with alpha3(IV) NC1. Failure of the intrathymic inoculation of antigen to prevent disease suggests that immunological tolerance cannot be achieved by this intervention, in contrast to other autoimmune conditions, and may imply independent roles for cellular and humoral nephritogenic pathways in anti-GBM nephritis.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Renal-Electrolyte and Hypertension Division, University of Pennsylvania Medical Center, Philadelphia, USA. abbate@irfmn.mnegri.it
authors.forename: M
authors.initials: M
authors.lastname: Abbate
authors.forename: R
authors.initials: R
authors.lastname: Kalluri
authors.forename: D
authors.initials: D
authors.lastname: Corna
authors.forename: N
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: R T
authors.initials: RT
authors.lastname: McCluskey
authors.forename: B G
authors.initials: BG
authors.lastname: Hudson
authors.forename: G
authors.initials: G
authors.lastname: Andres
authors.forename: C
authors.initials: C
authors.lastname: Zoja
authors.forename: G
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology*; D000906:Antibodies / Q000032:analysis; D000918:Antibody Specificity; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D007114:Immunization; D008168:Lung / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000209:etiology; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D000906:Antibodies; D003094:Collagen