Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists
Allosensitization does not increase the risk of xenoreactivity to α1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists
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DOI：
10.1097/01.tp.0000228907.12073.0b
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发表时间：
2006-08-15
期刊：
影响因子：
6.2
通讯作者：
Sachs, David H.
中科院分区：
文献类型：
--
作者：
Wong, Banny S.;Yamada, Kazuhiko;Sachs, David H.
背景最近可用的α 1，3-半乳糖基转移酶敲除（GalT-KO）小型猪已经消除了抗Gal抗体作为异种移植的主要障碍，可能使这种模式更接近临床应用。高度同种异体致敏的患者，他们接受合适的交叉配型阴性人体器官的前景很差，可能是第一批从猪器官异种移植中受益的患者。然而，存在关于同种异体反应性抗人类白细胞抗原（HLA）抗体对异种猪白细胞抗原（SLA）抗原的交叉反应性的问题。我们已经使用来自这些患者的血清对GalT-KO靶细胞研究了这个问题。方法.使用流式细胞术和补体依赖性细胞毒性（CDC）测定，我们测试了来自等待尸体肾同种异体移植的患者的一组88份人血清样品对以下细胞的反应性：1）人; 2）标准小型猪;和3）GalT-KO外周血淋巴细胞（PBL）和培养的内皮细胞。结果与标准猪相比，GalT-KO上的抗猪IgM和IgG抗体结合以及CDC显著减弱。未发现抗人群体反应性抗体（PRA）的程度与标准或GalT-KO小型猪的异种反应性之间存在相关性。用二硫苏糖醇（DTT）处理血清显示，针对GalT-KO猪的大部分剩余淋巴细胞毒性由预先形成的IgM抗体介导。具有高同种异体反应性但低抗GalT-KO异种反应性的患者容易被鉴定。结论.等待肾移植的高度同种异体致敏患者似乎与其非致敏队列相比没有增加异种致敏的风险，因此可能是使用GalT-KO猪供体进行异种移植的候选者。
Background. The recent availability of alpha 1,3-galactosyltransferase knockout (GalT-KO) miniature swine has eliminated anti-Gal antibodies as the major barrier to xenotransplantation, potentially bringing this modality closer to clinical application. Highly-allosensitized patients, who have poor prospects of receiving a suitable cross-match negative human organ, might be the first patients to benefit from xenotransplantation of porcine organs. However, concerns exist regarding crossreactivity of alloreactive anti-human leukocyte antigen (HLA) antibodies against xenogeneic swine leukocyte antigen (SLA) antigens. We have investigated this question using sera from such patients on GalT-KO target cells. Methods. Using flow cytometry and complement- dependent cytotoxicity (CDC) assays, we have tested a panel of 88 human serum samples from patients awaiting cadaveric renal allotransplantation for reactivity against: 1) human; 2) standard miniature swine; and 3) GalT-KO peripheral blood lymphocytes (PBL) and cultured endothelial cells. Results. Anti-swine IgM and IgG antibody binding, as well as CDC, were significantly attenuated on GalT-KO versus standard swine. No correlation was found between the degree of anti-human panel reactive antibodies (PRA) and xenoreactivity against either standard or GalT-KO miniature swine. Treatment of sera with dithiothreitol (DTT) showed that the majority of remaining lymphocytotoxicity against GalT-KO swine was mediated by preformed IgM antibodies. Patients with high alloreactivity but low anti-GalT-KO xenoreactivity were readily identified. Conclusions. Highly allosensitized patients awaiting renal transplants appear to be at no increased risk of xenosensitization over their non-sensitized cohorts, and could therefore be candidates for xenotransplantation using GalT-KO swine donors.