1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. 2 Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. 3 Address correspondence to: Mary Carmelle Philogene, Ph.D., Immunogenetics Laboratory, 2041 E. Monument Street, Baltimore, MD 21205.
Transplantation. 2014 Sep 27;98(6):660-5. doi: 10.1097/TP.0000000000000132.
Bortezomib has been used to reduce HLA antibody in patients either before transplantation or as treatment for antibody-mediated rejection (AMR). Reports on its efficacy show mixed results. The mechanism of action of this agent is via proteasome inhibition. The primary route of synthesis of HLA class I molecules is dependent on peptide generation by the proteasome, whereas that of class II is not. We observed a differential effect of bortezomib on class I versus class II antibody and hypothesized that this was related to a reduced expression of class I HLA antigens.
The effect of bortezomib on HLA antibody levels was evaluated in 13 patients who were desensitized for incompatible renal transplantation. We calculated the percent difference in HLA antibody level before and after bortezomib treatment and the impact of bortezomib on HLA expression in lymphocytes of healthy control subjects.
On average, the level of HLA class I donor-specific antibody (DSA) decreased by 32%, whereas that of class II DSA increased by 29%. In vitro bortezomib treatment of lymphocytes resulted in a mean decrease of 23% in MHC class I expression on B lymphocytes and no change (+1.08%) in MHC class II expression (P=0.0003). The amount of intracellular class I molecules was reduced by a mean of 29% with bortezomib.
These data indicate that bortezomib reduces HLA class I antibody more effectively than class II antibody. This difference may be due to the reduced expression of class I molecules resulting from treatment with this proteasome inhibitor.
硼替佐米已被用于降低移植前或抗体介导排斥反应（AMR）治疗患者的 HLA 抗体。其疗效报告显示结果喜忧参半。该药物的作用机制是通过蛋白酶体抑制。HLA Ⅰ类分子的主要合成途径依赖于蛋白酶体产生的肽，而Ⅱ类则不然。我们观察到硼替佐米对Ⅰ类与Ⅱ类抗体的作用存在差异，并假设这与Ⅰ类 HLA 抗原表达减少有关。
我们评估了硼替佐米对 13 名因不相容性肾移植而进行脱敏治疗的患者 HLA 抗体水平的影响。我们计算了硼替佐米治疗前后 HLA 抗体水平的百分比差异，以及硼替佐米对健康对照者淋巴细胞中 HLA 表达的影响。
平均而言，HLA Ⅰ类供体特异性抗体（DSA）水平下降 32%，而Ⅱ类 DSA 水平上升 29%。硼替佐米对淋巴细胞的体外治疗导致 B 淋巴细胞上 MHC Ⅰ类表达平均下降 23%，而 MHC Ⅱ类表达无变化（+1.08%，P=0.0003）。硼替佐米使细胞内Ⅰ类分子的含量平均减少 29%。
这些数据表明，硼替佐米降低 HLA Ⅰ类抗体的效果优于Ⅱ类抗体。这种差异可能是由于这种蛋白酶体抑制剂治疗导致Ⅰ类分子表达减少所致。
