TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes
TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes
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DOI：
10.1038/nm924
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发表时间：
2003-09-01
期刊：
影响因子：
82.9
通讯作者：
Chatenoud, L
中科院分区：
文献类型：
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作者：
Belghith, M;Bluestone, JA;Chatenoud, L
CD3特异性抗体在已形成的自身免疫中具有恢复自身耐受性的独特能力。它们可诱导非肥胖糖尿病（NOD）小鼠以及人类I型糖尿病中显性糖尿病的长期缓解。直到现在，其潜在机制仍不清楚。在此我们报道，用CD3ε特异性抗体治疗可诱导涉及CD4(+)CD25(+)细胞的可转移的T细胞介导的耐受性。然而，这些CD4(+)CD25(+) T细胞不同于控制生理性自身反应性的天然存在的调节性T细胞。CD3特异性抗体治疗可诱导缺乏此类调节细胞的NOD Cd28(-/-)小鼠的病情缓解。同时给予中和转化生长因子（TGF）-β特异性抗体可消除糖尿病的缓解。耐受小鼠的CD4(+) T细胞长期增加产生TGF -β，这进一步表明了TGF -β的核心作用。这些数据解释了CD3特异性抗体令人感兴趣的致耐受效应，并将其定位为第一种可临床应用的产生TGF -β的调节性CD4(+) T细胞的药理兴奋剂。
CD3-specific antibodies have the unique capacity to restore self-tolerance in established autoimmunity. They induce long-term remission of overt diabetes in nonobese diabetic (NOD) mice and in human type I diabetes. The underlying mechanisms had been unclear until now. Here we report that treatment with CD3epsilon-specific antibodies induces transferable T-cell-mediated tolerance involving CD4(+)CD25(+) cells. However, these CD4(+)CD25(+) T cells are distinct from naturally occurring regulatory T cells that control physiological autoreactivity. CD3-specific antibody treatment induced remission in NOD Cd28(-/-) mice that were devoid of such regulatory cells. Remission of diabetes was abrogated by coadministration of a neutralizing transforming growth factor (TGF)-beta-specific antibody. The central role of TGF-beta was further suggested by its increased, long-lasting production by CD4(+) T cells from tolerant mice. These data explain the intriguing tolerogenic effect of CD3-specific antibodies and position them as the first clinically applicable pharmacological stimulant of TGF-beta-producing regulatory CD4(+) T cells.