Martin Caroline, Plat Martine, Nerriére-Daguin Véronique, Coulon Flora, Uzbekova Svetlana, Venturi Eric, Condé Françoise, Hermel Jean-Michel, Hantraye Philippe, Tesson Laurent, Anegon Ignacio, Melchior Benoit, Peschanski Marc, Le Mauff Brigitte, Boeffard Françoise, Sergent-Tanguy Solène, Neveu Isabelle, Naveilhan Philippe, Soulillou Jean-Paul, Terqui Michel, Brachet Philippe, Vanhove Bernard
Institut de Transplantation et de Recherche en Transplantation, INSERM U643, CHU Hôtel Dieu, 30, Bld J Monnet, Nantes, France.
Transgenic Res. 2005 Aug;14(4):373-84. doi: 10.1007/s11248-004-7268-4.
The transplantation of fetal porcine neurons is a potential therapeutic strategy for the treatment of human neurodegenerative disorders. A major obstacle to xenotransplantation, however, is the immune-mediated rejection that is resistant to conventional immunosuppression. To determine whether genetically modified donor pig neurons could be used to deliver immunosuppressive proteins locally in the brain, transgenic pigs were developed that express the human T cell inhibitory molecule hCTLA4-Ig under the control of the neuron-specific enolase promoter. Expression was found in various areas of the brain of transgenic pigs, including the mesencephalon, hippocampus and cortex. Neurons from 28-day old embryos secreted hCTLA4-Ig in vitro and this resulted in a 50% reduction of the proliferative response of human T lymphocytes in xenogenic proliferation assays. Transgenic embryonic neurons also secreted hCTLA4-Ig and had developed normally in vivo several weeks after transplantation into the striatum of immunosuppressed rats that were used here to study the engraftment in the absence of immunity. In conclusion, these data show that neurons from our transgenic pigs express hCTLA4-Ig in situ and support the use of this material in future pre-clinical trials in neuron xenotransplantation.
移植胎猪神经元是治疗人类神经退行性疾病的一种潜在治疗策略。然而，异种移植的一个主要障碍是免疫介导的排斥反应，这种反应对传统免疫抑制具有抗性。为了确定基因改造的供体猪神经元是否可用于在脑内局部递送免疫抑制蛋白，我们培育了在神经元特异性烯醇化酶启动子控制下表达人T细胞抑制分子hCTLA4-Ig的转基因猪。在转基因猪脑的各个区域均发现有表达，包括中脑、海马和皮层。来自28日龄胚胎的神经元在体外分泌hCTLA4-Ig，这导致在异种增殖试验中人类T淋巴细胞的增殖反应降低了50%。转基因胚胎神经元也分泌hCTLA4-Ig，并且在移植到免疫抑制大鼠纹状体中数周后在体内正常发育，在此我们利用这些大鼠研究在无免疫情况下的植入情况。总之，这些数据表明我们转基因猪的神经元在原位表达hCTLA4-Ig，并支持在未来神经元异种移植的临床前试验中使用这种材料。
