Proteasome Inhibition Reduces Donor-Specific Antibody Levels
Proteasome Inhibition Reduces Donor-Specific Antibody Levels
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DOI：
10.1016/j.transproceed.2008.10.073
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发表时间：
2009-01-01
影响因子：
0.9
通讯作者：
Woodle, E. S.
中科院分区：
文献类型：
--
作者：
Everly, M. J.;Everly, J. J.;Woodle, E. S.
背景目前的抗体介导的排斥（AMR）疗法（静脉内免疫球蛋白、单采血液成分术、利妥昔单抗、多克隆抗体）不靶向产生一抗的B细胞，即浆细胞。我们报告的初步结果，从第一次临床经验与浆细胞靶向治疗硼替佐米。硼替佐米被美国食品和药物管理局批准用于治疗浆细胞肿瘤（多发性骨髓瘤）。混合急性细胞排斥反应（ACR）和AMR发作（根据Banff '97标准，2005年更新）的肾移植患者接受标准标签剂量的硼替佐米（1.3 mg/m2/剂× 4）治疗。通过一系列供体特异性抗HLA抗体（DSA）测定[Luminex/Labscreen珠]监测患者，并通过将荧光强度转换为等效可溶性荧光分子（MESF）进行定量。5例患者接受硼替佐米治疗。每例患者同时存在ACR。在每种情况下，硼替佐米治疗导致迅速ACR和AMR排斥逆转。所有患者的DSA水平均显著降低（1例随访时间较短的患者除外）。观察到的硼替佐米毒性包括一过性III级血小板减少症（1例患者）和轻度至中度恶心、呕吐和/或腹泻（3/5例患者）。未发现细菌感染。硼替佐米治疗可有效降低DSA水平并长期抑制。这些初步结果表明，蛋白酶体抑制提供了一种有效的手段，降低移植受体的HLA抗体水平。
Background. 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).Methods. 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).Results. 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.Conclusions. 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.