Westphal Sabine, Brinkmann Hanna, Kalupa Martina, Wilke Andrea, Seitz-Merwald Isabell, Penack Olaf
Department of Hematology, Oncology and Tumorimmunology, Charité Campus Virchow, Klinikum, Berlin, Germany.
Neovii Biotech, Gräfelfing, Germany.
Exp Hematol. 2014 Oct;42(10):875-82. doi: 10.1016/j.exphem.2014.07.260. Epub 2014 Jul 10.
In vivo T-cell depletion using anti-T-cell antibodies is a standard procedure during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical data demonstrate that in vivo T-cell depletion with the anti-CD52 monoclonal antibody Alemtuzumab is associated with increased relapse rates of hematologic malignancies after allo-HSCT, underlining the importance of donor T cells for graft versus tumor activity. In contrast, recent results suggest that in vivo T-cell depletion with rabbit anti-T-cell globulin (ATG) Fresenius is not associated with tumor relapse after allo-HSCT, raising the possibility that ATG mediates antitumor effects. However, data on ATG's ability to bind to tumor cells and on its effect on the induction of antibody-dependent cellular cytotoxicity (ADCC) are lacking. We used ATG Fresenius, which contains polyclonal rabbit IgG directed against the human T-lymphoma cell line Jurkat, to study relevant mechanisms of ATG-mediated antitumor effects, including ADCC, complement-dependent cytotoxicity, and induction of apoptosis. Based on the knowledge that Jurkat cells aberrantly express myeloid markers and B-cell markers, we hypothesized that rabbit ATG Fresenius binds to a variety of hematologic malignancies. We found that ATG specifically binds to a variety of hematologic malignancies including acute myeloid leukemia and B-cell lymphoma in a concentration-dependent manner. We demonstrate that ATG mediates antitumor activity, including induction of ADCC, complement-dependent cytotoxicity, and apoptosis, toward different hematologic malignancies. Our results contribute to a better understanding of the effects of ATG on posttransplant immunology in patients undergoing allo-HSCT.
在异基因造血干细胞移植（allo-HSCT）过程中，使用抗T细胞抗体进行体内T细胞清除是一种标准程序。临床数据表明，使用抗CD52单克隆抗体阿仑单抗进行体内T细胞清除与allo-HSCT后血液系统恶性肿瘤的复发率增加相关，这突出了供体T细胞对移植物抗肿瘤活性的重要性。相比之下，最近的结果表明，使用兔抗T细胞球蛋白（ATG）费森尤斯进行体内T细胞清除与allo-HSCT后的肿瘤复发无关，这增加了ATG介导抗肿瘤作用的可能性。然而，关于ATG与肿瘤细胞结合的能力及其对抗体依赖性细胞毒性（ADCC）诱导作用的数据尚缺乏。我们使用了含有针对人T淋巴瘤细胞系Jurkat的多克隆兔IgG的ATG费森尤斯，来研究ATG介导的抗肿瘤作用的相关机制，包括ADCC、补体依赖性细胞毒性和凋亡诱导。基于Jurkat细胞异常表达髓系标志物和B细胞标志物的认识，我们假设兔ATG费森尤斯能与多种血液系统恶性肿瘤结合。我们发现ATG以浓度依赖性方式特异性结合多种血液系统恶性肿瘤，包括急性髓系白血病和B细胞淋巴瘤。我们证明ATG对不同的血液系统恶性肿瘤介导抗肿瘤活性，包括诱导ADCC、补体依赖性细胞毒性和凋亡。我们的结果有助于更好地理解ATG对接受allo-HSCT患者移植后免疫学的影响。
