Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA.
Terasaki Research Institute, Los Angeles, CA.
Transplantation. 2020 Apr;104(4):856-863. doi: 10.1097/TP.0000000000002895.
Chronic antibody-mediated rejection (cAMR) results in the majority of renal allograft losses. Currently, there are no approved therapies. We recently reported on clinical use of tocilizumab (TCZ) for treatment of cAMR in HLA-sensitized kidney transplant patients. IgG1 and IgG3 subclasses of IgG are potent effectors of complement- and antibody-dependent cellular cytotoxicity, which are critical mediators of AMR. Here, we examined the impact of TCZ treatment for cAMR on total IgG, IgG1-4 subclasses, and anti-HLA-IgG (total and subclasses).
Archived plasma obtained pre- and post-TCZ treatment (8 mg/kg, 6×, monthly) from 12 cAMR patients who failed standard of care treatment with intravenous immune globulin + rituximab with or without plasma exchange were tested for total IgG and IgG1-4 by ELISA, anti-HLA-total IgG, IgG3 and IgG4, and donor-specific antibody by Luminex assay. Archived plasma from 14 cAMR patients treated with the standard of care were included as controls.
Total IgG and IgG1-3 were significantly reduced post-TCZ, whereas no reduction was seen post-treatment in the control group. Of 11 patients, 8 (73%) showed reduction of anti-HLA-total IgG and IgG3 post-TCZ, but this was not statistically significant.
TCZ reduced total IgG and IgG1-3 and anti-HLA-total IgG and IgG3 levels, suggesting that TCZ suppresses Ig production in B cells nonspecifically, likely through inhibition of interleukin 6-mediated signaling to B cells and plasma cells. This may be a contributing factor for the beneficial effect of TCZ on cAMR observed in this patient population.
慢性抗体介导的排斥反应（cAMR）导致大多数肾移植失败。目前尚无批准的治疗方法。我们最近报告了托珠单抗（TCZ）在 HLA 致敏肾移植患者中治疗 cAMR 的临床应用。IgG1 和 IgG3 亚类 IgG 是补体和抗体依赖性细胞毒性的有效效应物，是 AMR 的关键介质。在此，我们研究了 TCZ 治疗 cAMR 对总 IgG、IgG1-4 亚类和抗 HLA-IgG（总类和亚类）的影响。
从 12 例接受静脉免疫球蛋白+利妥昔单抗联合或不联合血浆置换标准治疗失败的 cAMR 患者的存档血浆中，检测 TCZ 治疗（8mg/kg，6×，每月）前后的总 IgG 和 IgG1-4，ELISA 法检测抗 HLA-总 IgG、IgG3 和 IgG4，Luminex 法检测供体特异性抗体。将 14 例接受标准治疗的 cAMR 患者的存档血浆作为对照。
TCZ 治疗后总 IgG 和 IgG1-3 显著降低，而对照组治疗后无降低。在 11 例患者中，8 例（73%）在 TCZ 治疗后抗 HLA-总 IgG 和 IgG3 降低，但无统计学意义。
TCZ 降低了总 IgG 和 IgG1-3 以及抗 HLA-总 IgG 和 IgG3 水平，提示 TCZ 非特异性抑制 B 细胞的 Ig 产生，可能通过抑制白细胞介素 6 介导的 B 细胞和浆细胞信号通路。这可能是 TCZ 对该患者人群中 cAMR 有益作用的一个促成因素。
