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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，并携带人类整个人类IgH基因和IgLk转基因。因此，人免疫球蛋白1不会引起异种免疫反应。我们观察到给予DES/DeGal(DES/DeGal)免疫球蛋白A1的KM小鼠系膜免疫球蛋白A沉积。本研究先用人工合成的IgA1铰链(糖链)肽免疫小鼠，然后再注射DES/DeGal IgA1，并对免疫前的效果进行了评价。将小鼠分为SHP组、5Ga1NAc-SHP组和非免疫组。免疫前两组分别皮下注射KLH偶联SHP或含5个GalNAc残基的KLH-5GalNAc-SHP，每2周皮下注射3次。最后一次预免后两周，每日给予DES/DeGal IgA1，共5周。用酶联免疫吸附试验检测血清中抗SHP和抗IgA1抗体水平。在最后一次注射IgA1的当天，进行肾活检。未免疫的小鼠肾小球系膜免疫球蛋白A沉积。在预免疫的小鼠中，13只SHP小鼠中有6只和4只GalNAc-SHP小鼠中有1只未检测到IgA沉积。SHP免疫组与未免疫组之间IgA沉积强度差异有统计学意义(P=0.003)。IgA沉积强度与抗SHP抗体滴度呈显著负相关(p=0.016)。这些结果提示，抗IgA1铰链多肽抗体在抑制肾小球IgA沉积中起作用。