Role of BAFF on immune reconstitution following B-cell depletive therapy for SLE

BAFF 在 B 细胞耗竭治疗 SLE 后免疫重建中的作用

基本信息

批准号：
21790947
负责人：
KAWABATA Daisuke
金额：
$ 2.75万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790947/
关键词：
SLE B細胞除去療法 BAFF DNase 免疫再構築

项目摘要

We have reported that cyclophosphamide (CY)-induced B cell depletion resulted in an expansion of pathogenic high-affinity DNA-reactive B cells of R4A-Tg mice, followed by an increase of serum levels of BAFF (B cell-activating factor). Neutralization of BAFF by BAFF-R-Ig (BAFF-receptor-immunoglobulin) prevented the expansion of high-affinity DNA-reactive B cells in the reconstituting repertoire. Further, we have shown that bovine pancreatic DNase (Bp-DNase) treatment resulted in a reduction of BAFF production in estrogen-treated R4A-Tg mice. In the current study, we showed that the treatment of R4A-Tg mice with i.p. injection of Bp-DNase diminished the expansion of pathogenic DNA-reactive B cells. In NZB/W F1 mice, serum BAFF levels were elevated as they developed nephritis. Elevated erum BAFF levels were associated with serum anti-dsDNA antibody titers. B-cell depletion induced clinical remission 2 weeks after CY injection, followed by a reduction of anti-dsDNA antibodies titers and proteinuria. Four weeks after CY treatment, we observed clinical relapse as they showed re-increase of serum anti-dsDNA antibody titers and proteinuria. We are now performing experiments to elucidate whether BAFF inhibition by BAFF-R-Ig or Bp-DNase during reconstitution could prevent clinical flare-ups in CY-treated NZB/W F1mice.

我们报道说，环磷酰胺（CY）诱导的B细胞耗竭导致R4A-TG小鼠的致病高亲和力DNA反应性B细胞扩大，然后血清BAFF水平升高（B细胞激活因子）。通过BAFF-R-Ig（Baff-topepor-rymunoglobulin）对BAFF进行中和，从而阻止了重建曲目中高亲和力DNA反应性B细胞的扩展。此外，我们已经表明，牛胰腺DNase（BP-DNase）治疗导致雌激素治疗的R4A-TG小鼠的BAFF产生减少。在当前的研究中，我们表明用i.p.对R4A-TG小鼠的治疗。注射BP-DNase减少了致病性DNA反应B细胞的膨胀。在NZB/W F1小鼠中，血清BAFF水平在出现肾炎时升高。 ERUM BAFF水平升高与血清抗DSDNA抗体滴度有关。 B细胞耗竭在CY注射后2周诱导临床缓解，然后减少抗DSDNA抗体滴度和蛋白尿。 CY处理后四个星期，我们观察到临床复发，因为它们显示出血清抗DSDNA抗体滴度和蛋白尿的重新添加。现在，我们正在进行实验，以阐明在重建过程中通过BAFF-R-Ig或BP-DNase抑制BAFF是否可以防止经CY处理的NZB/W F1MICE中的临床爆发。