Perry D K, Burns J M, Pollinger H S, Amiot B P, Gloor J M, Gores G J, Stegall M D
Division of Transplantation Surgery, Department of Surgery, von Leibig Transplant Center, Mayo CLinic College of Medicine, Rochester, MN, USA.
Am J Transplant. 2009 Jan;9(1):201-9. doi: 10.1111/j.1600-6143.2008.02461.x. Epub 2008 Oct 31.
Antibody production by normal plasma cells (PCs) against human leukocyte antigens (HLA) can be a major barrier to successful transplantation. We tested four reagents with possible activity against PCs (rituximab, polyclonal rabbit antithymocyte globulin (rATG), intravenous immunoglobulin (IVIG) and the proteasome inhibitor, bortezomib) to determine their ability to cause apoptosis of human bone marrow-derived PCs and subsequently block IgG secretion in vitro. IVIG, rituximab and rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG blocked antibody production. In contrast, bortezomib treatment led to PC apoptosis and thereby blocked anti-HLA and antitetanus IgG secretion in vitro. Two patients treated with bortezomib for humoral rejection after allogeneic kidney transplantation demonstrated a transient decrease in bone marrow PCs in vivo and persistent alterations in alloantibody specificities. Total IgG levels were unchanged. We conclude that proteasome activity is important for PC longevity and its inhibition may lead to new techniques of controlling antibody production in vivo.
正常浆细胞（PCs）产生针对人类白细胞抗原（HLA）的抗体可能是成功移植的主要障碍。我们测试了四种可能对浆细胞有活性的试剂（利妥昔单抗、多克隆兔抗胸腺细胞球蛋白（rATG）、静脉注射免疫球蛋白（IVIG）和蛋白酶体抑制剂硼替佐米），以确定它们在体外诱导人骨髓来源浆细胞凋亡并随后阻断IgG分泌的能力。IVIG、利妥昔单抗和rATG均未能诱导浆细胞凋亡，利妥昔单抗和rATG均未阻断抗体产生。相比之下，硼替佐米治疗导致浆细胞凋亡，从而在体外阻断抗HLA和抗破伤风IgG分泌。两名接受硼替佐米治疗同种异体肾移植后体液排斥反应的患者，体内骨髓浆细胞出现短暂减少，同种异体抗体特异性持续改变。总IgG水平未变。我们得出结论，蛋白酶体活性对浆细胞寿命很重要，抑制它可能会带来体内控制抗体产生的新技术。
