Department of Endocrinology and Diabetology, Angiology, Nephrology and Clinical Chemistry, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
Transpl Immunol. 2012 Jun;26(4):171-5. doi: 10.1016/j.trim.2012.01.002. Epub 2012 Feb 2.
Sensitization to human leukocyte antigen (HLA) prolongs waiting list time and reduces allograft survival in solid organ transplantation. Current strategies for pretransplant desensitization are based on B-cell depletion and extracorporeal treatment. The proteasome inhibitor bortezomib allows direct targeting of the antibody-producing plasma cell and has been used in antibody-mediated rejection (AMR) and recipient desensitization with varying results. Here, we report the effect of bortezomib preconditioning on HLA antibody titers and specificity in highly sensitized patients awaiting renal allograft transplantation.
Two highly sensitized patients awaiting third kidney transplantation were given one cycle of bortezomib (1.3 mg/m², days 1, 4, 8, 11), as part of recipient desensitization. Time-course and levels of anti-HLA antibodies, as well as specificity to previous transplant antigens were monitored by luminex technology. In addition, measles and tetanus toxoid immunoglobulin G (IgG) was measured.
Following bortezomib, overall changes in IgG levels were small and no sustained reduction in anti-HLA class I or II antibody levels was observed over more than 100 days of follow-up to both, donor specific and non-donor specific antigens. Moreover, anti-measles and -tetanus toxoid IgG levels remained unchanged.
Bortezomib preconditioning alone does not result in sustained reduction of HLA antibody levels or alter protective immunity in sensitized patients. This supports the notion, that bortezomib requires activation of plasma cells, as in AMR, to effectively reduce HLA antibody production. Hence, in a pretransplant setting, combination strategies may be required to derive benefit from proteasome inhibition.
人类白细胞抗原（HLA）致敏会延长等待移植名单的时间，并降低实体器官移植的移植物存活率。目前的移植前脱敏策略基于 B 细胞耗竭和体外治疗。蛋白酶体抑制剂硼替佐米可直接靶向产生抗体的浆细胞，已在抗体介导的排斥反应（AMR）和受者脱敏中得到应用，但结果不一。在此，我们报告了硼替佐米预处理对高度致敏的肾移植受者等待移植患者 HLA 抗体滴度和特异性的影响。
两名高度致敏的患者等待第三次肾移植，在接受受者脱敏治疗时，接受了一个疗程的硼替佐米（1.3mg/m²，第 1、4、8、11 天）。通过 Luminex 技术监测抗 HLA 抗体的时间过程和水平，以及特异性到先前移植抗原。此外，还测量了麻疹和破伤风类毒素 IgG。
硼替佐米治疗后，IgG 水平总体变化较小，且在 100 多天的随访中，未观察到对供体特异性和非供体特异性抗原的抗 HLA Ⅰ类或Ⅱ类抗体水平持续降低。此外，抗麻疹和破伤风类毒素 IgG 水平保持不变。
硼替佐米预处理本身不会导致 HLA 抗体水平持续降低，也不会改变致敏患者的保护性免疫。这支持了这样一种观点，即硼替佐米需要激活浆细胞，如在 AMR 中，才能有效地减少 HLA 抗体的产生。因此，在移植前，可能需要联合策略才能从蛋白酶体抑制中获益。
