Everly M J, Everly J J, Susskind B, Brailey P, Arend L J, Alloway R R, Roy-Chaudhury P, Govil A, Mogilishetty G, Rike A H, Cardi M, Wadih G, Brown E, Tevar A, Woodle E S
University of Cincinnati College of Medicine, and The Christ Hospital, Cincinnati, OH 45267-0558, USA.
Transplant Proc. 2009 Jan-Feb;41(1):105-7. doi: 10.1016/j.transproceed.2008.10.073.
Current antibody-mediated rejection (AMR) therapies (intravenous immunoglobulin, apheresis, rituximab, polyclonal antibodies) do not target the primary antibody producing B cells, that is, the plasma cell. We report the preliminary results from the first clinical experience with plasma cell targeted therapy with bortezomib. Bortezomib is approved by the US Food and Drug Administration for the treatment of plasma cell tumors (multiple myeloma).
Kidney transplant patients with mixed acute cellular rejection (ACR) and AMR episodes (by Banff '97 criteria, update 2005) were treated with bortezomib (1.3 mg/m(2) per dose x 4) at standard labeled doses. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF).
Five patients were treated with bortezomib. Each patient also had coexisting ACR. In each case, bortezomib treatment led to prompt ACR and AMR rejection reversal. DSA levels decreased significantly in all patients (except 1 patient who had short follow-up). Observed toxicities from bortezomib included a transient grade III thrombocytopenia (1 patient) and mild-to-moderate nausea, vomiting, and/or diarrhea (3/5 patients). Opportunistic infections were not observed.
Bortezomib therapy provides effective reduction in DSA levels with long-term suppression. These preliminary results indicate that proteasome inhibition provides an effective means for reducing HLA antibody levels in transplant recipients.
目前抗体介导的排斥反应（AMR）疗法（静脉注射免疫球蛋白、血液分离术、利妥昔单抗、多克隆抗体）并不针对产生抗体的主要B细胞，即浆细胞。我们报告了硼替佐米靶向浆细胞治疗的首例临床经验的初步结果。硼替佐米已被美国食品药品监督管理局批准用于治疗浆细胞肿瘤（多发性骨髓瘤）。
符合混合急性细胞排斥反应（ACR）和AMR发作（根据2005年更新的Banff '97标准）的肾移植患者，接受标准标记剂量的硼替佐米（每剂量1.3mg/m²×4）治疗。通过连续测定供体特异性抗HLA抗体（DSA）[Luminex/Labscreen微珠法]对患者进行监测，并通过转换为荧光强度至等效可溶性荧光分子（MESF）进行定量。
5例患者接受了硼替佐米治疗。每位患者均合并有ACR。在每种情况下，硼替佐米治疗均导致ACR和AMR排斥反应迅速逆转。所有患者的DSA水平均显著下降（1例随访时间短的患者除外）。观察到的硼替佐米毒性包括1例短暂的III级血小板减少症和3/5的患者出现轻至中度恶心、呕吐和/或腹泻。未观察到机会性感染。
硼替佐米治疗可有效降低DSA水平并实现长期抑制。这些初步结果表明，蛋白酶体抑制为降低移植受者体内HLA抗体水平提供了一种有效手段。
