Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with α3 chain of type IV collagen

Abstract

Experimental Goodpasture's syndrome in Wistar-Kyoto rats immunized with ␣3 chain of type IV collagen.Background. Glomerulonephritis and lung hemorrhage of autoimmune Goodpasture syndrome develop due to immune reactions against epitope(s) of the non-collagenous (NC1) domain of ␣3-chain of type IV collagen [␣3(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 ␣3(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 ␣3(IV) monomer, dimer, or hexamer, or with ␣3(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 ␣3(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 ␣3(IV) NC1 dimer or hexamer. Lesions were dose-dependent upon injections of 10 to 100 g dimer. The ␣3(IV) NC1 monomer induced less severe proteinuria and no crescents. Pulmonary hemorrhage was detectable in 35% of rats immunized with 25 to 100 g ␣3(IV) NC1 dimer; ␣3(IV) synthetic peptide (36 carboxyl terminal) did not induce disease. Rats injected intrathymically with up to 100 g ␣3(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 ␣3(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.

CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis

“…As in Goodpasture's disease, the development of nephritis is associated with both cellmediated and humoral immunity to the noncollagenous (NC1) domain of the α3 chain of type IV collagen, or α3(IV)NC1. Work from other groups using related models supports the idea that the main target antigen is generally the same in EAG as in Goodpasture's disease (23)(24)(25)(26). In addition, anti-GBM antibodies from rats and mice with EAG have been shown to be pathogenic in passive transfer experiments (27,28), demonstrating a role for humoral immunity in the development of EAG.…”

The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

“…tumor volume by CED at higher concentrations than could likely be achieved systemically, thereby bypassing possible concerns about bloodbrain barrier impermeability (30,31). As the CED technique becomes more refined and applied in clinical settings, prolonged localized delivery of T3 might allow long-term control of glioma growth and progression, whereas avoiding the autoimmune responses possible following long-term systemic administration (13,48). The identification of a dual mechanism of action of T3 in the present study, therefore, not only provides insight into the function of endogenous inhibitors of angiogenesis but also may help influence how patients are selected for such therapy and ultimately may suggest alternative ways to use such agents clinically.…”

Glomerulonephritis Induced by Recombinant Collagen IVα3 Chain Noncollagen Domain 1 Is Not Associated with Glomerular Basement Membrane Antibody: A Potential T Cell-Mediated Mechanism

“…In most models, the Ags were either purified native GBM proteins from other species or recombinant proteins expressed in mammalian cells that also closely resembled the native protein. In those models, Abs to endogenous GBM were uniformly induced (18,19,22,27). Although some models used peptides as Ags (22,25,26), only one group was successful in induction of glomerulonephritis using keyhole limpet hemocyanin-linked peptides (25).…”