Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates
Gene therapy to inhibit xenoantibody production using lentiviral vectors in non-human primates
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DOI：
10.1038/sj.gt.3302818
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发表时间：
2007-01-01
期刊：
影响因子：
5.1
通讯作者：
Kearns-Jonker, M.
中科院分区：
文献类型：
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作者：
Fischer-Lougheed, J. Y.;Tarantal, A. F.;Kearns-Jonker, M.
针对gal α 1，3 gal（gal）表位的异种抗体阻碍了猪组织用于异种移植，这一过程可能有助于克服人类器官供体短缺的问题。使用表达猪α 1，3GT（合成半乳糖碳水化合物的酶）的慢病毒载体，可以在α 1，3-半乳糖基转移酶（α 1，3GT）（/）小鼠中实现稳定的半乳糖嵌合体和对半乳糖（+）心脏的耐受性。在这项研究中，我们评估了是否可以在非人灵长类动物中使用慢病毒载体实现足以抑制抗gal异种抗体应答的嵌合。在亚致死照射后，用自体的α 1，3GT转导的骨髓（BM）移植恒河猴。比较了猴免疫缺陷病毒（SIV）和人类免疫缺陷病毒（HIV）-1衍生的慢病毒构建体。在所有猴的几个造血谱系中观察到嵌合体。在移植后的前2个月，接受基于SIV的α 1，3GT构建体的动物中的移植与使用HIV-1衍生的慢病毒载体实现的移植相似，但此后增加至5个月达到更高水平。在用猪肝细胞免疫后，与对照相比，在gal（+）BM受体中抗gal免疫球蛋白M异种抗体的产生显著减少。这项研究是第一次报告应用基因治疗，以实现低水平，长期的半乳糖嵌合体足以抑制生产后，猪细胞免疫恒河猴抗半乳糖抗体。
Xenoantibodies to the gal alpha 1,3 gal (gal) epitope impede the use of pig tissues for xenotransplantation, a procedure that may help overcome the shortage of human organ donors. Stable gal chimerism and tolerance to gal(+) hearts could be achieved in alpha 1,3-galactosyltransferase (alpha 1,3GT) (/) mice using lentiviral vectors expressing porcine alpha 1,3GT, the enzyme that synthesizes the gal carbohydrate. In this study, we evaluated whether chimerism sufficient to inhibit anti-gal xenoantibody responses can be achieved using lentivectors in non-human primates. Rhesus macaques were transplanted with autologous, alpha 1,3GT-transduced bone marrow (BM) following sublethal irradation. Simian immunodeficiency virus (SIV)- and human immunodeficiency virus (HIV)-1-derived lentiviral constructs were compared. Chimerism was observed in several hematopoietic lineages in all monkeys. Engraftment in animals receiving SIV-based alpha 1,3GT constructs was similar to that achieved using the HIV-1-derived lentivector for the first 2 months post-transplantation, but increased thereafter to reach higher levels by 5 months. Upon immunization with porcine hepatocytes, the production of anti-gal immunoglobulin M xenoantibody was substantially reduced in the gal(+) BM recipients compared to controls. This study is the first to report the application of gene therapy to achieve low-level, long-term gal chimerism sufficient to inhibit production of anti-gal antibodies after immunization with porcine cells in rhesus macaques.