Imlifidase Inhibits HLA Antibody-mediated NK Cell Activation and Antibody-dependent Cell-mediated Cytotoxicity (ADCC) In Vitro
Imlifidase Inhibits HLA Antibody-mediated NK Cell Activation and Antibody-dependent Cell-mediated Cytotoxicity (ADCC) In Vitro
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DOI：
10.1097/tp.0000000000003023
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发表时间：
2020-08-01
期刊：
影响因子：
6.2
通讯作者：
Toyoda, Mieko
中科院分区：
文献类型：
--
作者：
Ge, Shili;Chu, Maggie;Toyoda, Mieko
背景资料。抗体依赖细胞介导的细胞毒(ADCC)是导致抗体介导排斥反应(AMR)的重要途径。Imlifidase(IDES)将人的免疫球蛋白切割成F(ab‘)(2)和Fc片段，潜在地抑制ADCC。在此，我们研究了IDES在体外对同种抗体介导的NK细胞激活(Allo-CFC)和ADCC的影响。方法：研究方法。对于Allo-CFCs，将正常全血与经抗人类白细胞抗原抗体阳性(HS)或阴性(NC)血清处理的第三方外周血单核细胞(PBMC)孵育，检测干扰素-γ+NK细胞百分比。对于ADCC，将正常PBMC与含有HS或NC血清的Farage B(FB)细胞孵育，测定7-AAD+裂解FB细胞百分率。为了评价IDES对上述检测结果的影响，将经血清处理的PBMCs(Allo-CFC-1)、用于PBMC前处理的血清(Allo-CFC-2)和用于ADCC的血清与IDES预先孵育。接受IDES治疗的患者的血清也进行了异种氟氯化碳(Allo-CFC-3)检测。结果。HS患者外周血中干扰素-γ-NK细胞百分率显著高于正常对照组(10+/-3%比2+/-1%，P=0.001)，异基因-氟氯化碳-2(20+/-10%比4+/-2%)和7AAD+FB细胞%(11+/-3%比4+/-2%，P=0.001)。经IDES处理后，这些指标显著降低。抗HLA抗体水平在脂酶后1天显著降低的患者血清失去激活Allo-CFC-3中NK细胞的能力，但在脂酶后1-3个月的患者血清恢复了激活NK细胞的能力。结论。在体外和治疗后，IDES均能抑制NK细胞的活化和ADCC。这些结果和报道的IDES对补体激活的抗人类白细胞抗原抗体的抑制表明它可能在AMR的治疗中发挥作用。
Background. Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important pathway responsible for antibody-mediated rejection (AMR). Imlifidase (IdeS) cleaves human IgG into F(ab')(2)and Fc fragments, potentially inhibiting ADCC. Here we examined the effect of IdeS on allo-antibody-mediated NK cell activation (Allo-CFC) and ADCC in vitro. Methods. For Allo-CFC, normal whole blood was incubated with third-party peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody positive (HS) or negative (NC) sera to measure IFN gamma+ NK cell%. For ADCC, normal PBMCs were incubated with Farage B (FB) cells with HS or NC sera to measure 7-AAD+ lysed FB cell%. To assess the effect of IdeS on these assays, serum-treated PBMCs (Allo-CFC-1) and serum used for PBMC pretreatment (Allo-CFC-2) in Allo-CFC, and serum used for ADCC were preincubated with IdeS. Sera from IdeS-treated patients were also tested for Allo-CFC (Allo-CFC-3). Results. IFN gamma+ NK cell% were significantly elevated in HS versus NC sera in Allo-CFC-1 (10 +/- 3% versus 2 +/- 1%,P= 0.001), Allo-CFC-2 (20 +/- 10% versus 4 +/- 2%,P= 0.01) and 7AAD+ FB cell% (11 +/- 3% versus 4 +/- 2%,P= 0.02) in ADCC. These were significantly reduced by IdeS treatment. Patient sera with significantly reduced anti-HLA antibody levels at 1 day postimlifidase lost the capacity to activate NK cells in Allo-CFC-3, but those at 1-3 months postimlifidase regained the capacity. Conclusions. IdeS inhibited NK cell activation and ADCC in vitro and in treated patients. These results and reported inhibition of complement activating anti-HLA antibodies by IdeS suggest its possible role in treatment of AMR.