| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
A Th2-type immune response has recently been suggested to play an important role in the mechanism of pathogenesis of IgA nephropathy, including the hygiene hypothesis. We have therefore studied the mechanism of IgA production and deposition using GATA-3 transgenic (GATA-3 Tg) mice into which transcription factor GATA-3 related to the Th2 type immunity inducement gene. After intraperitoneal immunization with ovalbumin (OVA) and alum as the adjuvant, despite a significant increase in serum levels of IgA antibody, no histopathological and urinary findings suggesting IgA nephropathy were observed. However, after oral immunization with cholera toxin, which possesses adjuvant activity for mucosal immunity, deposition of IgA, IgG and C3 similar to that in association with human IgA nephropathy as well as expansion of the matrix accompanying proliferation of mesangial cells were observed, in addition to a significant increase in serum levels of IgA antibody. In order to assess the mechanism of
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this IgA deposition in terms of cytokine expression, we evaluated the amount of Thl and Th2 cytokines produced in the Peyer's patch, mesenteric lymph nodes and spleen in response to OVA restimulation in vitro in GATA-3 Tg mice receiving OVA and cholera toxin orally.(1) In the spleen, tolerance to Thl-type immune response was induced after oral administration of OVA. This immune tolerance induced regulation of Thl-type immune responses by IL-4.(2) While the disruption of immune tolerance was observed in mice receiving OVA and CT, Thl-type immune responses in inhibition of TGF-beta production and in production of IL-2 and IFN-gamma were normalized.(3) A correlation with the positive rate of interstitial CD4+CD25+T cells in the spleen in the immunohistological study was observed.
Thus, the experiment result indicated that a regulation of the Th1/Th2 balance via mucosal immunity is involved in the mechanism of the pathogenesis of IgA nephropathy. The finding and result indicate that the mice and the system we generated can serve as useful tools to identify causative substances for IgA nephropathy and analyze more detailed mechanism of the pathogenesis. Less
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