Investigations of pathogenesis and therapeutic approach for IgA nephropathy.-A trial of experimental mouse model of glomerular deposition of human IgA-

IgA肾病发病机制和治疗方法的研究-人IgA肾小球沉积实验小鼠模型的试验-

基本信息

批准号：
16590804
负责人：
HIKI Yoshiyuki
金额：
$ 2.18万
依托单位：
Fujita Health University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

The KM mouse lacks endogenous genes for immunoglobulins and carries the human entire human IgH locus and the IgLk transgene. Therefore, human IgA1 does not provoke a hetero-immune response. We had observed mesangial IgA deposits in KM mice given desialo-degalacto (DeS/DeGal) IgA1. In this study, the mice were immunized with synthetic IgA1 hinge (glyco-)peptide before administration of DeS/DeGal IgA1, and the effects of the pre-immunization were evaluated. Mice were divided into sHP, 5Ga1NAc-sHP and non-immunization groups. In two pre-immunization groups, KLH-conjugated sHP or KLH-5GalNAc-sHP, which has five GalNAc residues, was subcutaneously given three times every two weeks. Two weeks after the final pre-immunization, DeS/DeGal IgA1 was daily administered for five weeks. Serial serum levels of anti-sHP and anti-IgA1antibodies were evaluated by ELISA. On the day of the last administration of IgA1, renal biopsy was performed. Mesangial IgA deposits were observed in all non-immunized mice. In pre-immunized mice, IgA deposition was not detected in six of 13 sHP mice and one of four 5GalNAc-sHP mice. The intensities of IgA deposits were significantly different between sHP groups and non-immunized (p=0.003) groups. There was a significant inverse correlation between the intensities of IgA deposits and the anti-sHP antibody titers (p=0.016). These results suggest that the anti-IgA1 hinge peptide antibody plays a role in the inhibition of glomerular IgA deposition.

KM 小鼠缺乏免疫球蛋白的内源基因，并携带人类完整的 IgH 基因座和 IgLk 转基因。因此，人类 IgA1 不会引起异种免疫反应。我们在给予去唾液酸-去半乳 (DeS/DeGal) IgA1 的 KM 小鼠中观察到系膜 IgA 沉积。在本研究中，在给予DeS/DeGal IgA1之前用合成的IgA1铰链（糖）肽对小鼠进行免疫，并评估预免疫的效果。将小鼠分为sHP组、5Ga1NAc-sHP组和非免疫组。在两个预免疫组中，每两周皮下注射3次KLH缀合的sHP或具有5个GalNAc残基的KLH-5GalNAc-sHP。最后一次预免疫两周后，每天施用 DeS/DeGal IgA1，持续五周。通过 ELISA 评估抗 sHP 和抗 IgA1 抗体的连续血清水平。在最后一次给予 IgA1 的当天，进行肾活检。在所有未免疫小鼠中均观察到系膜 IgA 沉积。在预免疫小鼠中，13 只 sHP 小鼠中的 6 只和 4 只 5GalNAc-sHP 小鼠中的 1 只未检测到 IgA 沉积。 sHP 组和未免疫组之间 IgA 沉积的强度显着不同 (p=0.003)。 IgA 沉积强度和抗 sHP 抗体滴度之间存在显着的负相关 (p=0.016)。这些结果表明抗IgA1铰链肽抗体在抑制肾小球IgA沉积中发挥作用。