Depletion of IgM xenoreactive natural antibodies by injection of anti-mu monoclonal antibodies.
Depletion of IgM xenoreactive natural antibodies by injection of anti-mu monoclonal antibodies.
复制标题
通过注射抗 mu 单克隆抗体消除 IgM 异种反应性天然抗体。
DOI：
10.1111/j.1600-065x.1994.tb00874.x
复制
发表时间：
1994
影响因子：
8.7
通讯作者：
Bazin,H
中科院分区：
文献类型：
--
作者：
Latinne,D;Soares,M;Havaux,X;Cormont,F;Lesnikoski,B;Bach,FH;Bazin,H
免疫球蛋白M异种反应性天然抗体(XNA)和补体的激活被认为是猪到灵长类动物肾、肝或心脏移植等非协调性异种移植超急性排斥反应(HAR)的两个主要效应因子。我们假设，长期耗尽循环中的IgM XNA可能能够克服HAR，并诱导猪到灵长类血管不协调的异种移植物的“适应”。已经描述了几种技术来消除灵长类动物体内循环的XNA，但到目前为止，还没有一种技术能够在足够长的时间内完全耗尽这些抗体，以检验不和谐异种移植物“适应”的假说。我们实验室以前的报告表明，在啮齿类动物中，B细胞免疫抑制可以通过新生儿注射抗MU抗体来实现。最近我们发现，在成年大鼠体内注射抗MU单抗，能够完全耗尽循环中的IgM和IgM XNA，而不会出现免疫复合体疾病。此外，我们还采用了脾切除、血浆置换和抗B细胞免疫抑制剂霉酚酸酯(RS61443，Syntex，美国帕洛阿尔托)等不同的方法，在给予抗MU单抗(MARM-7)之前预排空循环IgM，结果表明，抗MU单抗清除循环Ig M的效果提高了100倍。以抗MU单抗(MARM-7)去除成年大鼠循环中的IgM为实验模型，研究了IgM-XNA在豚鼠-大鼠心脏异种移植HAR发病机制中的作用。我们的数据显示，IgM XNA在HAR中发挥着重要作用，即使在这种不协调的组合中，补体的直接激活似乎是HAR的主要效应者，可能是通过替代途径。我们分析了成年动物抗MU耗竭循环IgM的机制，结果表明，除抗MU/Ig M免疫复合物的形成外，循环Ig M的耗竭是由于体内交联剂和B细胞表面Ig M内化后对B细胞分化和分泌Ig M的非常显著的抑制所致。此外，我们提供的证据表明，抗Mu单抗在B细胞成熟的早期阶段就会阻断B细胞，可能是在骨髓中。此外，我们还研制了几种大鼠抗人和抗狒狒的IgM单抗，并测试了它们在脾切除或脾切除和血浆置换后对狒狒循环中的IgM和IgM XNA的清除能力。
It is believed that IgM xenoreactive natural antibodies (XNA) and activation of complement are the two main effectors involved in the hyperacute rejection (HAR) of discordant xenografts, such as pig-to-primate kidney, liver or heart transplants. We have hypothesized that long-term depletion of circulating IgM XNA might be able to overcome HAR and induce the" accommodation" of pig-to-primate vascular discordant xenografts. Several techniques have been described to eliminate circulating XNA in primates but, up to now, none has been able to totally deplete these antibodies for a sufficiently long period of time in order to test the hypothesis of discordant xenograft" accommodation". Previous reports from our laboratory have shown that, in rodents, B-cell immunosuppression could be achieved by neonatal administration of anti-mu antibodies. Recently we have shown that administration of an anti-mu mAb, in adult rats, was able to totally deplete circulating IgM and IgM XNA, without immune complex disease. Furthermore, we have used different methods such as splenectomy, plasma exchange and an anti-B cell immunosuppressive agent mycophenylate mophetil (RS61443, Syntex, Palo Alto, USA) to pre-deplete circulating IgM before administration of anti-mu mAb (MARM-7) and showed that the effectiveness of anti-mu mAb to deplete circulating IgM was increased by 100-fold. Depletion of circulating IgM in adult rats by anti-mu mAb (MARM-7) was used as an experimental model to study the role of IgM XNA in the pathogenesis of HAR in guinea pig-to-rat cardiac xenografts. Our data show that IgM XNA play a major role in HAR, even if in this discordant combination direct activation of complement, probably through the alternative pathway, seems to be the main effector involved in HAR. We have analyzed the mechanisms of anti-mu depletion of circulating IgM in adult animals and shown that, besides anti-mu/IgM immune complex formation, depletion of circulating IgM results from the very significant inhibition of B-cell differentiation and secretion of IgM following in vivo crosslinking and internalization of surface IgM on B cells. As well, we provide evidence demonstrating that anti-mu mAb blocks B cells at an early stage of maturation, probably in the bone marrow. Furthermore, we have developed several rat anti-human and anti-baboon IgM mAb and tested their ability to deplete circulating IgM and IgM XNA in baboons, after splenectomy or splenectomy and plasma exchange.(ABSTRACT TRUNCATED AT 400 WORDS)