Retargeting of Human Regulatory T Cells by Single-Chain Bispecific Antibodies
Retargeting of Human Regulatory T Cells by Single-Chain Bispecific Antibodies
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DOI：
10.4049/jimmunol.1101760
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Bachmann, Michael
中科院分区：
文献类型：
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作者：
Koristka, Stefanie;Cartellieri, Marc;Bachmann, Michael
双特异性抗体在恶性疾病的免疫治疗中具有很大的潜力。由于这类新药的第一批成分现在正在进入临床试验，因此应该很好地了解它们的作用模式的方方面面。多项研究证明，CD8(+)和CD4(+)效应性T细胞在体内外均能被双特异性抗体成功地重定向和激活，以对抗肿瘤细胞。据我们所知，这项研究提供了第一个证据，表明双特异性抗体也可以重定向和激活针对表面抗原的调节性T细胞，而不依赖于它们的TCR特异性。通过双特异性抗体进行交联后，重定向的调节性T细胞上调激活标记CD69和CD25，以及调节性T细胞相关标记，如CTLA-4和FOXP3。被激活的调节性T细胞分泌免疫抑制细胞因子IL-10，但与CD8(+)和CD4(+)效应T细胞相比，几乎没有炎性细胞因子。此外，重定向的调节性T细胞能够在体外和体内抑制激活的自体CD4(+)T细胞的效应器功能。因此，在应用双特异性抗体治疗恶性肿瘤时，应考虑调节性T细胞激活的潜在风险。相反，利用双特异性抗体对调节T细胞进行抗原/组织特异性重定向，在治疗自身免疫性疾病和移植物排斥反应方面具有巨大的潜力。免疫学杂志，2012,188：1551-1558。
Bispecific Abs hold great potential for immunotherapy of malignant diseases. Because the first components of this new drug class are now entering clinical trials, all aspects of their mode of action should be well understood. Several studies proved that CD8(+) and CD4(+) effector T cells can be successfully redirected and activated against tumor cells by bispecific Abs both in vitro and in vivo. To our knowledge, this study provides the first evidence that bispecific Abs can also redirect and activate regulatory T cells against a surface Ag, independently of their TCR specificity. After cross-linking, via a bispecific Ab, redirected regulatory T cells upregulate the activation markers CD69 and CD25, as well as regulatory T cell- associated markers, like CTLA-4 and FOXP3. The activated regulatory T cells secrete the immunosuppressive cytokine IL-10, but, in contrast to CD8(+) and CD4(+) effector T cells, almost no inflammatory cytokines. In addition, the redirected regulatory T cells are able to suppress effector functions of activated autologous CD4(+) T cells both in vitro and in vivo. Therefore, the potential risk for activation of regulatory T cells should be taken into consideration when bispecific Abs are applied for the treatment of malignant diseases. In contrast, an Ag/tissue-specific redirection of regulatory T cells with bispecific Abs holds great potential for the treatment of autoimmune diseases and graft rejection. The Journal of Immunology, 2012, 188: 1551-1558.