Department of Surgery, University of Cincinnati College of Medicine, Ohio, USA.
Curr Opin Organ Transplant. 2009 Dec;14(6):662-6. doi: 10.1097/MOT.0b013e328330f304.
The purpose of this review is to describe the biochemistry and physiology of proteasome inhibition and to discuss recent studies with proteasome inhibitor therapy in organ transplantation.
Traditional antihumoral therapies do not deplete plasma cells, the source of antibody production. Proteasome inhibition depletes both transformed and nontransformed plasma cells in animal models and human transplant recipients. Bortezomib is a first in a class proteasome inhibitor that has been shown to effectively treat antibody-mediated rejection in kidney transplant recipients. In this experience, bortezomib provided reversal of histologic changes and also induced a reduction in donor-specific anti-HLA antibody levels. Recent experiences have also shown that bortezomib reduces donor-specific anti-human leukocyte antigen antibody in the absence of rejection. Finally, evidence has been presented that bortezomib therapy depletes human leukocyte antigen-specific antibody producing plasma cells.
Proteasome inhibition induces a complex series of biochemical events that results in pleiotropic effects on multiple cell populations, and plasma cells in particular. Initial clinical results have provided evidence that bortezomib effectively treats antibody-mediated rejection and acute cellular rejection and reduces or eliminates donor-specific anti-human leukocyte antigen antibody. Carefully designed clinical trials are needed to accurately define the role of proteasome inhibition in transplant recipients.
本文旨在描述蛋白酶体抑制的生物化学和生理学，并讨论蛋白酶体抑制剂在器官移植中的最新研究进展。
传统的抗体液治疗并不能耗尽浆细胞，而浆细胞是抗体产生的来源。在动物模型和人类移植受者中，蛋白酶体抑制不仅能耗竭转化后的浆细胞，也能耗竭未转化的浆细胞。硼替佐米是一种首创的蛋白酶体抑制剂，已被证明能有效治疗肾移植受者的抗体介导的排斥反应。在这一经验中，硼替佐米不仅逆转了组织学变化，还诱导了供体特异性抗 HLA 抗体水平的降低。最近的经验还表明，硼替佐米在没有排斥反应的情况下也能降低供体特异性抗人类白细胞抗原抗体。最后，有证据表明硼替佐米治疗能耗竭人类白细胞抗原特异性抗体产生的浆细胞。
蛋白酶体抑制诱导了一系列复杂的生化事件，对多种细胞群体产生多效性影响，特别是浆细胞。初步的临床结果提供了证据，表明硼替佐米能有效治疗抗体介导的排斥反应和急性细胞排斥反应，并降低或消除供体特异性抗人类白细胞抗原抗体。需要精心设计临床试验来准确确定蛋白酶体抑制在移植受者中的作用。
