Selective IgM depletion prolongs organ survival in an ex vivo model of pig-to-human xenotransplantation.
Selective IgM depletion prolongs organ survival in an ex vivo model of pig-to-human xenotransplantation.
复制标题
在猪对人异种移植的离体模型中，选择性 IgM 消耗可延长器官存活率。
DOI：
10.1097/00007890-199607150-00002
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发表时间：
1996
期刊：
影响因子：
6.2
通讯作者：
Dalmasso,AP
中科院分区：
文献类型：
--
作者：
Kroshus,TJ;Bolman3rd,RM;Dalmasso,AP
在猪-灵长类动物模型中，异种移植物超急性排斥反应（HAR）由抗体和补体介导。以往的研究表明，异种反应性IgM天然抗体（nAb）是参与HAR的主要免疫球蛋白。为了进一步评估IgM的作用，我们选择性地降低人血液中的IgM水平，而不改变IgG和伊加水平，然后使用该血液离体灌注猪心。使用含有与琼脂糖凝胶珠缀合的羊抗人IgM（μ链特异性）的免疫吸附柱完成特异性IgM消除。人血被分离成血浆和细胞成分。对于对照实验，这些成分未经修改并在灌注系统中重新组合。对于IgM减少的血液的实验，使血浆通过IgM柱。通过ELISA测量，免疫吸收导致异种反应性IgM水平降低约90%。用未修饰的人血灌注的猪心存活25±5.6 min（n= 5）。用含有降低水平IgM的人血灌注的猪心存活229± 45.2min（n= 4; P< 0.01）。器官存活率与灌注前即刻测量的异种反应性IgM nAb水平呈负相关（r=-0.83; P= 0.01），而与IgG nAb水平无关（r=-0.21; P= 0.62）。通过iC 3b与猪主动脉内皮细胞的体外结合测量，来自IgM耗尽血液的血浆引起补体活化的能力也与IgM异种反应性nAb水平强烈相关（r= 0.92; P< 0.0001）。用未修饰的人血灌注的对照心脏显示出典型的广泛的HAR组织学特征，而用IgM减少的血液灌注的猪心显示出较温和和较不均匀的变化。每项研究完成时获得的心脏组织的免疫病理学分析显示，两组之间IgG沉积相似，但IgM减少组中IgM、C3、C4和C9明显减少。这些结果表明，选择性IgM减少延迟HAR与生存期延长，异种反应性IgM可能是主要的免疫球蛋白参与HAR的猪-人组合。
In the pig-to-primate model, xenograft hyperacute rejection (HAR) is mediated by antibody and complement. Previous studies have implicated xenoreactive IgM natural antibody (nAb) as the predominant immunoglobulin involved in HAR. To further evaluate the role of IgM, we selectively reduced IgM levels in human blood, without changing IgG and IgA levels, and then used this blood to perfuse porcine hearts ex vivo. Specific IgM depletion was accomplished with an immunoabsorption column containing sheep anti-human IgM (μ-chain specific) conjugated to Sepharose beads. Human blood was separated into plasma and cellular components. For control experiments, those components were unmodified and recombined in the perfusion system. For experiments with IgM reduced blood, the plasma was passed through the IgM column. Immunoabsorption resulted in≈ 90% reduction in xenoreactive IgM levels, as measured by ELISA. Porcine hearts perfused with unmodified human blood survived 25±5.6 min (n= 5). Porcine hearts perfused with human blood containing reduced levels of IgM survived 229±45.2 min (n= 4; P< 0.01). Organ survival was negatively associated with xenoreactive IgM nAb levels measured immediately before perfusion (r=-0.83; P= 0.01), and not with IgG nAb levels (r=-0.21; P= 0.62). The ability of plasma from IgM-depleted blood to elicit complement activation, measured by iC3b binding to porcine aortic endothelial cells in vitro, was also strongly associated with IgM xenoreactive nAb levels (r= 0.92; P< 0.0001). Control hearts perfused with unmodified human blood showed typical widespread histologic features of HAR, while porcine hearts perfused with IgM-reduced blood demonstrated milder and less uniform changes. Immunopathological analysis of heart tissues obtained at the completion of each study showed similar deposition of IgG between groups but markedly less IgM, C3, C4, and C9 in the IgM reduction group. These results suggest that selective IgM reduction delays HAR with prolongation of survival and that xenoreactive IgM may be the predominant immunoglobulin involved in HAR in the pig-to-human combination.