Neonatal Thymectomy Diminishes Renal IgA Deposition in IgA Nephropathy-Prone ddY Mice

Nagasawa, Ryo; Mitarai, Tetsuya; Utsunomiya, Yasunori; Yoshida, Hiroaki; Kitamura, Masanori; Yamura, Wako; Maruyama, Naoki; Isoda, Kazuo; Sakai, Osamu

doi:10.1159/000187831

Cited by 6 publications

(3 citation statements)

References 14 publications

(14 reference statements)

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“…Another study demonstrated an increased CD4/CD8 ratio in IgA nephropathy patients, and that depletion of CD8+ cells results in decreased IgA production in vitro [26]. In ddY mice, neonatal thymectomy or CD4+ cell depletion by monoclonal anti-CD4 antibodies diminished IgA deposition in the glomerulus [27, 28]. The present study showed that the number of CD3+ cells was significantly reduced in young HIGA mice.…”

Section: Discussionsupporting

confidence: 59%

Up-Regulated TGF-β mRNA Expression in Splenic T Cells of High IgA-Prone Mice: A Murine Model of IgA Nephropathy with Glomerulosclerosis

Oyama

Muso

Ono

et al. 2001

Nephron

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Background/Aims: Recently, we established a high serum IgA-prone inbred (HIGA) mouse strain as a murine model of spontaneous IgA nephropathy by selective mating of high serum IgA ddY mice, and found that they showed enhanced production of glomerular extracellular matrix components with increased expression of TGF-β mRNA and protein in the kidneys. In this study, we examined the roles of lymphocytes in the development of high serum IgA in this strain. Methods: We performed flow cytometric analyses of T and B cells in splenic mononuclear cells (SMNCs) from these mice using BALB/c mice as normal controls. We also compared serum TGF-β1 concentrations and TGF-β mRNA expression levels in the B-cell-depleted (T-cell-rich) fraction of SMNCs in these mice. Results: HIGA mice showed significantly fewer CD3-positive cells compared with BALB/c mice when young, but not when aged. The CD4/CD8 ratio of HIGA mice was lower than that of BALB/c mice, but this difference was not significant. Although the number of B220-positive cells did not vary significantly, the ratio of surface IgA-positive B cells was significantly increased in both young and adult HIGA mice. The B-cell-depleted SMNCs from HIGA mice exhibited higher levels of expression of TGF-β and TGF-β1 mRNA than controls from a young age, which were maintained throughout life, but there were no differences in PDGF, MCP-1 or bFGF expression between these two strains. In contrast to local mRNA expression, serum TGF-β1 concentration was decreased in HIGA mice compared with BALB/c controls. Conclusion: These findings suggest that the mating procedure performed to establish HIGA mice selected for a unique phenotype of local up-regulation of TGF-β production in the kidneys, as well as T cells that may contribute to both the early and consistently high serum IgA expression and enhanced production of renal extracellular matrix components in HIGA mice. Additionally, TGF-β1 may act locally, not systemically, in a paracrine or autocrine manner.

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Section: Discussionsupporting

confidence: 59%

Up-Regulated TGF-β mRNA Expression in Splenic T Cells of High IgA-Prone Mice: A Murine Model of IgA Nephropathy with Glomerulosclerosis

Oyama

Muso

Ono

et al. 2001

Nephron

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“…However, there is no evidence for a direct role of CD4+ and CD8+ T cells in causing injury of glomeruli in IgA nephropathy. In this regard, Nagasawa et al [13] demonstrated recently that thymectomy during neonatal life reduced renal IgA deposition in ddY mice. On the other hand, immunofluorescence examination of renal tissues following the administration of anti-CD4 mAb showed a reduction of IgA deposits in the mesangium, but such treatment failed to suppress the proliferation of mesangial cells in ddY mice [14].…”

Section: Discussionmentioning

confidence: 99%

Anti-CD8 Monoclonal Antibody Protects against Spontaneous IgA Nephropathy in ddY Mice

Shimamine¹,

Shibata²,

Ozono³

et al. 1998

Nephron

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We investigated the effects of anti-CD4 monoclonal antibody (mAb) and/or anti-CD8 mAb in ddY mice, an animal model of spontaneous IgA nephropathy. Female ddY mice were treated with 18 intravenous injections of anti-CD4 and/or anti-CD8 mAb at 2-week intervals. This was based on our observation that a single injection of anti-CD4 mAb or anti-CD8 mAb caused a selective depletion in CD4+ T cells for 2 weeks and CD8+ T cells for 4 weeks, respectively. The level of proteinuria, serum IgA, and changes in the histopathological features of renal tissue samples were assessed in treated mice between the age of 4 and 40 weeks. The level of proteinuria increased with age, but there was not significant difference among the groups. No animal developed microhematuria throughout the study. Treatment with anti-CD4 mAb produced a mild to moderate level of mesangial hypertrophy at 20 and 40 weeks, similar to the results in untreated mice. The lowest degree of mesangial hypertrophy occurred in mice treated with anti-CD8 mAb up to the age of 40 weeks. Treatment with a combination of anti-CD4 and anti-CD8 mAbs produced effects that were similar to those observed on treatment with anti-CD8 mAb alone. Our results suggest that CD8+ T cells mediate mesangial proliferation and the progression of nephropathy in ddY mice.

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“…Neonatal thymectomy of ddY mice that develop IgAN spontaneously ameliorates the disease [86]. This effect is predicted from the importance of T cell help for Ig class switching and for B cell differentiation.…”

Section: T Cell Regulation and Cytokine Polaritymentioning

confidence: 99%

Prospects and Perspectives on IgA Nephropathy from Animal Models

Emancipator

2011

Contributions to Nephrology

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The focus of this chapter is a systematic and critical review of the insights that experimental models have contributed to our understanding of IgA nephropathy (IgAN). We consider the generation of IgA subject to glomerular deposition, the partitioning of IgA between the circulation and glomeruli, the clearance of IgA and complexes containing IgA from the circulation, the 'upstream' effectors of glomerular pathophysiology, the inflammatory mediators that connect intraglomerular stimuli to functional and morphologic effects, and the contribution of animal models to our current understanding of the role that glycosylation of IgA plays in the genesis of IgAN. In each of these subsections, the evidence in favor of each principle or hypothesis is weighed in consideration of other potentially contradictory evidence and relevant issues related to IgAN in patients. The key limitations of each model system are presented, and where possible, reconciliation of discrepant observations are proposed. Subsequently, a synopsis of spontaneous models that do not offer particular mechanistic insights, and a compilation of experimental therapeutic initiatives, are reviewed. In all respects, the discussion of observations in patients or cells in vitro is limited to points where these data impinge upon interpretation of the data derived from the animal models.

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Neonatal Thymectomy Diminishes Renal IgA Deposition in IgA Nephropathy-Prone ddY Mice

Cited by 6 publications

References 14 publications

Up-Regulated TGF-β mRNA Expression in Splenic T Cells of High IgA-Prone Mice: A Murine Model of IgA Nephropathy with Glomerulosclerosis

Up-Regulated TGF-β mRNA Expression in Splenic T Cells of High IgA-Prone Mice: A Murine Model of IgA Nephropathy with Glomerulosclerosis

Anti-CD8 Monoclonal Antibody Protects against Spontaneous IgA Nephropathy in ddY Mice

Prospects and Perspectives on IgA Nephropathy from Animal Models

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