Current status of pig kidney xenotransplantation.
Current status of pig kidney xenotransplantation.
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DOI：
10.1016/j.ijsu.2015.07.721
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
Kobayashi T
中科院分区：
文献类型：
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作者：
Iwase H;Kobayashi T
非人灵长类动物（NHP）中维持生命的异种肾移植物存活率的显著进展在很大程度上与越来越多的具有遗传修饰的猪的可用性相关，这些遗传修饰保护猪组织免受灵长类动物免疫应答和/或纠正猪与灵长类动物之间的分子不相容性。抗CD 154 mAb治疗阻断CD 40/CD 154共刺激途径有助于延长肾脏异种移植物的生存期，尽管这种药物可能无法在临床上使用。基于抗CD 40 mAb的方案被证明同样成功，但CD 28/B7通路的阻断是不够的。在猪肾异种移植的早期研究中，一致记录了严重的蛋白尿，但这是否是由于免疫损伤或物种之间的生理不相容性，或两者兼而有之，仍然不确定。最近的实验表明，这与持续的免疫反应有关。在2014年之前，NHP中猪肾移植的最长存活期为90天，尽管移植物存活>30天是不寻常的。最近这已经延长到>125天，没有消耗性凝血病或蛋白丢失性肾病的特征。总之，通过在供体猪中开发精确的遗传修饰来克服免疫、凝血和炎症反应，沿着有效的免疫抑制和抗凝/抗炎治疗正在将该领域推向临床试验。
Significant progress in life-supporting kidney xenograft survival in nonhuman primates (NHPs) has been associated largely with the increasing availability of pigs with genetic modifications that protect the pig tissues from the primate immune response and/or correct molecular incompatibilities between pig and primate. Blockade of the CD40/CD154 costimulation pathway with anti-CD154 mAb therapy has contributed to prolongation of kidney xenograft survival, although this agent may not be clinically available. An anti-CD40 mAb-based regimen is proving equally successful, but blockade of the CD28/B7 pathway is inadequate. Severe proteinuria were uniformly documented in the early studies of pig kidney xenotransplantation, but whether this resulted from immune injury or from physiological incompatibilities between the species, or both, remained uncertain. Recent experiments suggest it was related to a continuing immune response. Before 2014, the longest survival of a pig kidney graft in a NHP was 90 days, though graft survival >30 days was unusual. Recently this has been extended to >125 days, without features of a consumptive coagulopathy or a protein-losing nephropathy. In conclusion, overcoming the immune, coagulation, and inflammatory responses by the development of precise genetic modifications in donor pigs, along with effective immunosuppressive and anticoagulant/anti-inflammatory therapy is advancing the field towards clinical trials.