High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis

• Published in: Kidney international Vol. 66; no. 1; pp. 177 - 186
• Main Authors: Kohda, Takayuki, Okada, Shin-Ichi, Hayashi, Atsushi, Kanzaki, Susumu, Ninomiya, Yoshifumi, Taki, Masafumi, Sado, Yoshikazu
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.07.2004; Nature Publishing; Elsevier Limited
• Subjects: Animals; anti-GBM nephritis; Anti-Glomerular Basement Membrane Disease - immunology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - immunology; Autoantibodies - immunology; Biological and medical sciences; Collagen Type IV - immunology; dose-effect relationship; Dose-Response Relationship, Drug; Female; Fluorescent Antibody Technique; Hemorrhage - immunology; IgG subclass; Immunoglobulin G - immunology; Lung Diseases - immunology; Medical sciences; monoclonal autoantibody; Nephrology. Urinary tract diseases; Protein Structure, Tertiary; pulmonary hemorrhage; Rats; Rats, Inbred WKY; Severity of Illness Index; type IV collagen; type IV collagen; pulmonary hemorrhage; dose-effect relationship; anti-GBM nephritis; monoclonal autoantibody; IgG subclass; Kidney disease; High; Nephrology; Urinary system disease; Rat; Rodentia; Monoclonal antibody; Urology; Vertebrata; Mammalia; Nephropathy; Animal; monoclonal autoantihody
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1111/j.1523-1755.2004.00719.x

High nephritogenicity of monoclonal antibodies belonging to IgG2a and IgG2b subclasses in rat anti-GBM nephritis. To examine a subclass-effect relationship and a dose-effect relationship of autoantibodies in the rat antiglomerular basement membrane (GBM) antibody-induced glomerulonephritis (anti-GBM nephritis) model, we injected homologous monoclonal antibodies against the NC1 domains of rat type IV collagen into inbred Wistar-Kyoto (WKY) rats. Eight different autoantibodies from each of the IgG1, IgG2a, and IgG2b subclasses were established and administered to groups of four WKY rats at a dose of 300 μg/rat. To examine the dose-effect relationship, we administered 0 to 300 μg/rat of autoantibodies from each subclass to rats. All IgG1 antibodies induced mild nephritis, whereas the IgG2a and IgG2b antibodies induced moderate to severe nephritis. Some IgG2a and IgG2b antibodies induced pulmonary hemorrhage as well. These antibodies were reactive with α3(IV)NC1, α4(IV)NC1, or α5(IV)NC1. The minimum dose of antibody required to induce nephritis was 30 μg/rat for IgG1, 3 μg/rat for IgG2a, and 1 μg/rat for IgG2b. At doses of 30 μg/rat or less, antibody deposition was generally restricted to the GBM. At doses of 100 μg/rat or greater, antibody deposition extended to both the GBM and tubular basement membrane (TBM). Pulmonary hemorrhage was observed only when a large amount of pulmonary hemorrhagic antibody was administered. The severity of nephritis was dependent on both subclass and dose of autoantibodies. It becomes clear that pulmonary hemorrhage in anti-GBM nephritis is induced by autoantibodies.