Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model
Tolerance induction by the blockade of CD40/CD154 interaction in pemphigus vulgaris mouse model
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DOI：
10.1038/sj.jid.5700016
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发表时间：
2006-01-01
影响因子：
6.5
通讯作者：
Amagai, Masayuki
中科院分区：
文献类型：
--
作者：
Aoki-Ota, Miyo;Kinoshita, Mari;Amagai, Masayuki
寻常天疱疮（PV）是由抗桥粒芯糖蛋白3（Dsg 3）的IgG自身抗体引起的自身免疫性起泡疾病。我们最近通过过继转移Dsg 3（-/-）小鼠的脾细胞开发了PV的活动性疾病小鼠模型。本研究的目的是确定CD 40/CD 154相互作用在PV模型小鼠的致病性抗体产生和疾病发展中的作用。当在过继转移之前向受体小鼠施用抗CD 154单克隆抗体（mAb）时，抗CD 154 mAb几乎完全阻断抗Dsg 3 IgG的产生并防止水疱形成。CD 40/CD 154相互作用的阻断诱导了对Dsg 3的耐受性，因为直到第70天观察到抗体产生的抑制，并且即使在用重组小鼠Dsg 3免疫或通过过继转移免疫的Dsg 3（-/-）脾细胞进行攻击后，该耐受性也得以维持。此外，对Dsg 3的耐受性是可转移的，因为来自抗CD 154 mAb处理的小鼠的脾细胞和初始Dsg 3（-/-）脾细胞的共转移显著抑制了受体小鼠中抗Dsg 3 IgG的产生。相反，当在小鼠发展PV表型后注射抗CD 154 mAb时，未观察到抗Dsg 3 IgG产生的显著抑制。这些发现表明，CD 40/CD 154相互作用对于诱导致病性抗Dsg 3 IgG抗体是必不可少的，并且由抗CD 154 mAb诱导的抗原特异性免疫调节细胞将为自身免疫性疾病提供治疗选择。
Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3(-/-) mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti- Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3(-/-) splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naive Dsg3(-/-) splenocytes significantly suppressed anti- Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti- Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti- Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.