A novel mechanism of action for anti-thymocyte globulin:: Induction of CD4+CD25+Foxp3+ regulatory T cells
A novel mechanism of action for anti-thymocyte globulin:: Induction of CD4+CD25+Foxp3+ regulatory T cells
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DOI：
10.1681/asn.2006050422
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发表时间：
2006-10-01
影响因子：
13.6
通讯作者：
Najafian, Nader
中科院分区：
文献类型：
--
作者：
Lopez, Marta;Clarkson, Michael R.;Najafian, Nader
T细胞耗竭剂正在测试作为临床耐受性策略的一部分，在人类自身免疫和移植。抗甲状腺细胞球蛋白（ATG）的免疫抑制活性被认为主要来自外周淋巴细胞的耗竭。本文首次报道了当与人外周血淋巴细胞一起培养时，ATG而不是抗CD 52 mAb（阿仑单抗）或IL-21 Z拮抗剂导致CD 4（+）CD 25（+）T细胞快速和持续扩增。这些细胞表现出调节标志物糖皮质激素诱导的TNF受体、细胞毒性T淋巴细胞相关抗原-4（CTLA-4）和叉头框P3的表达增强，并有效地抑制原始应答淋巴细胞的直接同种免疫应答。有趣的是，这些细胞并不抑制对回忆抗原腮腺炎的记忆反应。调节性T细胞的离体扩增主要是由于CD 4（+）CD 25（+）转化为CD 4（+）CD 25（+）T细胞，以及天然CD 4（+）CD 25（+）T细胞的较小程度的增殖。调节性T细胞的诱导依赖于产生培养物中Th 2细胞因子的产生。这些新的数据表明，ATG不仅可以促进调节性T细胞的扩增/产生，而且还可以用于这些细胞的未来离体扩增，用于自身免疫和临床移植中的细胞治疗。
T cell-depleting agents are being tested as part of clinical tolerance strategies in humans with autoimmunity and transplantation. The immunosuppressive activity of anti-thyrnocyte globulin (ATG) has been thought to result primarily from depletion of peripheral lymphocytes. Herein is reported for the first time that ATG but not anti-CD52 mAb (alemtuzumab) or the IL-21Z antagonists causes rapid and sustained expansion of CD4(+)CD25(+) T cells when cultured with human peripheral blood lymphocytes. These cells display enhanced expression of the regulatory markers glucocorticoid-induced TNF receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and forkhead box P3 and efficiently suppress a direct alloimmune response of the original responder lymphocytes. It is interesting that the cells do not suppress memory responses to the recall antigen mumps. Ex vivo expansion of regulatory T cells is due mainly to conversion of CD4(+)CD25(+) into CD4(+)CD25(+) T cells and to a lesser degree to proliferation of natural CD4(+)CD25(+) T cells. The induction of regulatory T cells depends on production of Th2 cytokines in the generating cultures. These novel data suggest that ATG not only may promote expansion/ generation of regulatory T cells but also may be useful in future ex vivo expansion of these cells for cellular therapy in autoirnmunity and clinical transplantation.