生物人工肝治疗后接触猪肝细胞的肝衰竭患者体内人异种反应性抗体的特征：猪到人的异种移植的体外模型
Characterization of human xenoreactive antibodies in liver failure patients exposed to pig hepatocytes after bioartificial liver treatment: an ex vivo model of pig to human xenotransplantation.
作者信息
Baquerizo A, Mhoyan A, Kearns-Jonker M, Arnaout W S, Shackleton C, Busuttil R W, Demetriou A A, Cramer D V
机构信息
Center for Liver Diseases and Transplantation, Department of Surgery, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
出版信息
Transplantation. 1999 Jan 15;67(1):5-18. doi: 10.1097/00007890-199901150-00003.
BACKGROUND
There are limited experimental data on the nature of the humoral response elicited in humans against pig antigens. In this study, we have examined the xenoantibody (XAb) response in eight patients with acute liver failure exposed to pig hepatocytes after treatment with the bioartificial liver (BAL).
METHODS
Patients' plasma samples obtained before and after BAL treatment were tested for IgM and IgG XAbs, IgG subclasses, and XAb cytotoxicity, using enzyme-linked immunosorbent assay and flow-cytometric assays. The characterization of pig aortic endothelial cell (PAEC) surface xenoantigens was analyzed by immunoprecipitation.
RESULTS
We observed by day 10, a strong anti-pig IgG and IgM XAb response in patients undergoing two or more BAL treatments, with a significant increase in all the IgG subclasses; in contrast, XAb titers did not change if the patients received only one BAL treatment. The majority of the XAbs produced to porcine antigens were primarily specific for the alphaGal epitope. Both IgG and IgM XAbs were cytotoxic to PAECs, and the cytotoxic activity of IgG was associated with high levels of IgG1 and IgG3 subclasses, known to be efficient on complement activation. The characterization of porcine surface antigens demonstrated that IgM human XAbs, before and after BAL exposure, recognized xenoantigens on PAECs with similar molecular weights, suggesting that the same population of XAbs were present in the patients before and after exposure to pig antigens.
CONCLUSIONS
Repetitive exposure of humans to porcine antigens after BAL treatment, results in a strong IgG and IgM XAb responses that are primarily directed against the alphaGal epitope. These XAbs are cytotoxic to PAECs and the IgG toxicity correlates with high IgG1 and IgG3 levels. Our data also suggest that no new XAb specificity emerges after porcine exposure.
背景
关于人类针对猪抗原引发的体液免疫反应的性质，实验数据有限。在本研究中，我们检测了8例急性肝衰竭患者在接受生物人工肝（BAL）治疗后接触猪肝细胞时的异种抗体（XAb）反应。
方法
使用酶联免疫吸附测定法和流式细胞术测定法，检测BAL治疗前后患者血浆样本中的IgM和IgG XAb、IgG亚类以及XAb细胞毒性。通过免疫沉淀分析猪主动脉内皮细胞（PAEC）表面异种抗原的特征。
结果
我们观察到，在接受两次或更多次BAL治疗的患者中，到第10天时出现了强烈的抗猪IgG和IgM XAb反应，所有IgG亚类均显著增加；相比之下，如果患者仅接受一次BAL治疗，XAb滴度则没有变化。针对猪抗原产生的大多数XAb主要对αGal表位具有特异性。IgG和IgM XAb对PAEC均具有细胞毒性，且IgG的细胞毒性活性与高水平的IgG1和IgG3亚类相关，已知这两种亚类在补体激活方面效率较高。猪表面抗原的特征表明，BAL暴露前后，人类IgM XAb识别PAEC上分子量相似的异种抗原，这表明在接触猪抗原前后，患者体内存在相同群体的XAb。
结论
人类在BAL治疗后反复接触猪抗原，会导致强烈的IgG和IgM XAb反应，主要针对αGal表位。这些XAb对PAEC具有细胞毒性，且IgG毒性与高IgG1和IgG3水平相关。我们的数据还表明，接触猪抗原后不会出现新的XAb特异性。
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