Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis.
Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis.
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DOI：
10.1084/jem.20051060
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发表时间：
2005-08-01
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CD4+CD25+调节性T细胞（T reg细胞）在控制自身免疫和炎症中起关键作用。因此，非常需要能够提高该T细胞亚群的数量或增加其效应子功能的治疗剂。在以前的报告中，我们表明，一个超激动剂的单克隆抗体特异性大鼠CD28（JJ316）的扩展和激活T reg细胞在体内和短期体外培养。在这里，我们证明了将非常低剂量的CD 28超激动剂应用于正常刘易斯大鼠足以诱导体内T reg细胞扩增，而没有用高剂量的JJ316观察到的全身性淋巴细胞增多。对患有实验性自身免疫性脑脊髓炎（EAE）的黑琼脂糖（DA）大鼠或刘易斯大鼠单次静脉内给予低剂量的CD 28超激动剂证明与高剂量治疗具有高度和同等的有效性。最后，我们表明，T reg细胞，从CD28处理的动物分离显示增强抑制活性髓鞘碱性蛋白特异性T细胞在体外，过继转移后，保护受体EAE。我们的数据表明，这类CD28特异性单克隆抗体靶向CD4+CD25+ T reg细胞，为有效治疗多发性硬化症和其他自身免疫性疾病提供了一种新的手段。
CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.