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

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.

Immunosuppressive and Anti-Inflammatory Effects of Nicotine Administered by Patch in an Animal Model

“…Thus, NTP-induced changes in inflammation might explain some of the "beneficial" effects of smoking. The Lewis rat has been used as an experimental animal model for many inflammatory and autoimmune diseases (10,21,40,41,46,47), and the transdermal NTP could be used to test the therapeutic potential of NT for various inflammatory diseases.…”

Downregulation of a pathogenic autoantibody response by IgM autoantibodies directed against the nephritogenic antigen in slowly progressive Heymann nephritis

“…HN has a rapid and irreversible course and therefore it is not suitable for testing new treatment options. Previous work has shown that none of the pre‐ or post‐disease treatment protocols could significantly influence the three most important aspects of HN development that contribute to its establishment, namely pathogenic aab formation, progressive immune complex glomerulonephritis (ICGN) and proteinuria development 11–20 …”

Down‐regulation of pathogenic autoantibody response in a slowly progressive Heymann nephritis kidney disease model

“…Treatment of this autoimmune kidney disease has been attempted by several means, but so far, no treatment options have held the promise of a cure Barabas et al 1970;Kupor et al 1976;Cattran 1988;Matsukawa et al 1992;Gilkeson et al 1996;Penny et al 1998;Yokoyama et al 1999;Hasegawa et al 2001). Indeed, researchers have tried various medications for this and other experimental animal autoimmune disorders.…”

“…Indeed, researchers have tried various medications for this and other experimental animal autoimmune disorders. While certain treatments instituted before the occurrence of the disease have led to lessened morphological and functional changes Barabas et al 1970;Bagchus et al 1986;Nangaku et al 1996;Schiller et al 1998;Rieben et al 1999;Hasegawa et al 2001;Spicer et al 2001), treating animals in advanced disease stages has not altered eventual outcome. As solutions for treating autoimmune disorders in humans must come from animal experiments, there is considerable urgency to find specific treatments which might terminate such disease conditions.…”