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      Suppression of Experimental Membranous Glomerulonephritis in Rats by an Anti-MHC Class II Antibody

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          Abstract

          Background: We previously reported that idiopathic membranous nephropathy (IMN) strongly correlated with HLA-DRB1*1501-DRB5*0101-DQAI*0102-DQB1* 0602, a specific haplotype of human major histocompatibility complex (MHC), in Japanese patients. To investigate the role of MHC in the development of rat Heymann nephritis (HN), an animal model of membranous nephropathy, a monoclonal antibody (mAb) specific to rat MHC class II antigen (RT1B) was administered, and its effectiveness in inhibiting HN was assessed. Methods: Active HN was induced in HN-sensitive Lewis rats by administering brush border proteins of rat proximal uriniferous tubules (FX1A). Rats were divided into four groups: rats treated with 1,000 µg anti-rat MHC class II mAb, rats treated with 100 µg anti-rat MHC class II mAb, rats treated with murine myeloma IgG, and rats that did not receive either FX1A or any other mAb. We examined the differences in 24-hour urinary protein excretion and serum alloantibody titers against FX1A between groups at different time intervals, and the histologic features of kidneys at the end of the study. Results: HN was induced in Lewis rats by inoculation with FX1A antigen. Administration of anti-MHC class II mAb successfully lowered urinary proteins, production of anti-FX1A alloantibodies, and the development of glomerular lesions in a dose-dependent manner. Conclusion: The present results demonstrated that the MHC class II molecule itself is directly involved in the pathogenesis of HN, and suggest that this therapy would be any better (or less toxic) than nonselective immunosuppressants in the treatment of IMN.

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          Most cited references 2

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          Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats

          The nephritogenic antigen of Heymann's nephritis (HN) was previously purified from tubular brush-border fractions of rat kidney and found to be a 330,000- mol-wt glycoprotein (gp330). This study was conducted to determine whether gp330 is also present in the rat glomerulus, and, if so, to establish where in the glomerulus it is located. Rabbit polyclonal and mouse monoclonal antibodies were raised against purified gp330, which specifically immunoprecipitated gp330 from solubilized brush-border fractions and specifically stained microvilli and coated invaginations (located at the base of the microvilli) of proximal tubule cells. Accordingly, they were used to localize gp330 by immunoprecipitation and immunocytochemistry in glomeruli of normal Lewis rats. For immunoprecipitation, purified glomerular fractions were prepared from [(35)S]-methionine-labeled kidneys, extracted with Triton X-100, and the extract was used for immunoprecipitation with affinity-purified rabbit polyclonal, or mouse monoclonal, anti-gp330 IgG. Analysis of immunoprecipitates by sodium dodecyl sulfate-polyacrylamide gel electrophoresis fluorography indicated that a band corresponding in mobility to gp330 was specifically precipitated. When unfixed cryostat sections were incubated for indirect immunofluorescence with monoclonal or affinity-purified polyclonal IgG, a fine granular fluorescent staining was seen throughout the glomerulus. When aldehyde-fixed cryostat sections were incubated for indirect immunoperoxidase, reaction product was detected only in the epithelial cells and was not seen in the GBM, endothelium, or mesangium. Within the epithelium it was localized to the endoplasmic reticulum, occasional Golgi elements, multivesicular bodies, and coated pits at the cell surface. The reactive coated pits were distributed all along the cell membrane, including the sides and base of the foot processes. Reaction product was detected in the latter location only in sections that had been digested with neuraminidase before antibody incubation. When rats were given rabbit anti-gp330 IgG by intravenous injection and their kidneys stained for direct immunoperoxidase 3 d later, rabbit IgG was seen to be deposited beneath the slit diaphragms and in the coated pits at the base of the foot processes. The immunocytochemical and immunoprecipitation data indicate, in confirmation of the results of others, that the nephritogenic HN antigen is present in renal glomeruli as well as in proximal tubular brush borders. The immunocytochemical results further demonstrate that gp330 is an epithelial, rather than a glomerular basement membrane, antigen. It appears to be synthesized by glomerular epithelial cells and subsequently becomes concentrated in coated pits. As both the endogenous antigen (gp330) and exogenously administered anti-gp330 antibody were localized to coated pits, it seems likely that coated pits located at the base of the foot processes are the sites where the HN antigen (gp330) and circulating antibodies directed against gp330 meet and where immune complexes are formed.
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            Association between HLA-DRB1*15 and Japanese Patients with Rheumatoid Arthritis Complicated by Renal Involvement

            We performed serological phenotyping of HLA antigens in 175 patients with rheumatoid arthritis (RA) with (n = 41) and without (n = 134) renal involvement (RI), and DNA typing of HLA class II alleles in 75 patients. Among the patients with RA, the frequency of serologically determined HLA-DR4 was found to be significantly increased (odds ratio: 1.8, confidence interval: 1.3–2.5, p = 2.4×10 –4 ). In the patients without RI, the frequency of serological DR4 significantly increased (odds ratio: 2.2, confidence interval: 1.6–3.3, p = 2.6×10 –5 ). On the other hand, among the patients with RI, a serological determinant, DR15, did significantly increase (odds ratio: 2.7, confidence interval: 0.9–8.4, p = 1.2×10 –3 ) in comparison to the controls. At the DNA level, we found that the association of Japanese RA patients with serological HLA-DR4 was based on that with a genotype of HLA-DRB1*0405 (odds ratio: 2.4, confidence interval: 1.5–4.0, p = 4.4×10 –4 ) and also found an association of HLA-DRB1*1501 (odds ratio: 2.8, confidence interval: 1.2–6.6, p = 0.017) with RA patients having RI. Our results confirmed the association of HLA-DRB1*04 with RA over the ethnic barrier at the DNA level. Our results also suggested a distinct genetic effect of HLA-DRB1*1501 in the aspect of the susceptibility of RI in RA.
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              Author and article information

              Journal
              NEF
              Nephron
              10.1159/issn.1660-8151
              Nephron
              S. Karger AG
              1660-8151
              2235-3186
              2001
              2001
              22 June 2001
              : 88
              : 3
              : 233-240
              Affiliations
              Fukuoka University Hospital Kidney Center, Fukuoka, Japan
              Article
              45995 Nephron 2001;88:233–240
              10.1159/000045995
              11423754
              © 2001 S. Karger AG, Basel

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              Page count
              Figures: 5, Tables: 2, References: 55, Pages: 8
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/45995
              Categories
              Original Paper

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