Long-term discordant xenogeneic (porcine-to-primate) bone marrow engraftment in a monkey treated with porcine-specific growth factors
Long-term discordant xenogeneic (porcine-to-primate) bone marrow engraftment in a monkey treated with porcine-specific growth factors
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DOI：
10.1097/00007890-199904150-00007
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发表时间：
1999-04-15
期刊：
影响因子：
6.2
通讯作者：
Sachs, DH
中科院分区：
文献类型：
--
作者：
Sablinski, T;Emery, DW;Sachs, DH
背景混合异基因造血嵌合体先前已被可靠地实现，并显示在小鼠和猴中诱导对完全MHC错配的同种异体移植物的耐受。然而，在不协调的猪-灵长类异种模型中，造血嵌合体的建立一直难以实现。为了解决这个问题，在输注猪骨髓（BM）前6天和5天，通过全身照射（总剂量300 cGy）对两只食蟹猴进行了条件反射。在静脉输注猪BM前（第0天），通过猪肝体外灌注猴血，免疫吸附猴抗猪天然抗体。给予环孢素4周，15-脱氧精胍菌素2周。一只猴子接受重组猪细胞因子（干细胞因子和白细胞介素3）2周，而另一只接受生理盐水作为对照。两只猴在全身照射后4周内从全血细胞减少症中恢复。抗猪IgM和IgG抗体通过肝脏灌注成功耗尽，但在12-14天内恢复到治疗前水平。在第180天和第300天的甲基纤维素集落测定显示，在经精氨酸处理的受体的BM中约2%的髓样祖细胞是猪来源的，而在类似时间在未经处理的对照猴的BM中未检测到嵌合体。嵌合体动物对猪特异性刺激物的混合淋巴细胞反应比对照猴的反应更低，并且与排斥猪肾移植的猴相比反应明显降低。据我们所知，这是第一次报告的长期生存的不协调异种骨髓在灵长类动物受体。
Background. Mixed allogeneic hematopoietic chimerism has previously been reliably achieved and shown to induce tolerance to fully MHC-mismatched allografts in mice and monkeys. However, the establishment of hematopoietic chimerism has been difficult to achieve in the discordant pig-to-primate xenogeneic model.Methods. To address this issue, two cynomolgus monkeys were conditioned by whole body irradiation (total dose 300 cGy) 6 and 5 days before the infusion of pig bone marrow (BM), Monkey anti-pig natural antibodies were immunoadsorbed by extracorporeal perfusion of monkey blood through a pig liver, immediately before the intravenous infusion of porcine BM (day 0). Cyclosporine was administered for 4 weeks and 15-deoxyspergualin for 2 weeks. One monkey received recombinant pig cytokines (stem cell factor and interleukin 3) for 2 weeks, whereas the other received only saline as a control.Results. Both monkeys recovered from pancytopenia within 4 weeks of whole body irradiation. Anti-pig IgM and IgG antibodies were successfully depleted by the liver perfusion but returned to pretreatment levels within 12-14 days. Methylcellulose colony assays at days 180 and 300 revealed that about 2% of the myeloid progenitors in the BM of the cytokine-treated recipient were of pig origin, whereas no chimerism was detected in the BM of the untreated control monkey at similar times. The chimeric animal was less responsive by mixed lymphocyte reaction to pig-specific stimulators than the control monkey and significantly hyporesponsive when compared with a monkey that had rejected a porcine kidney transplant.Conclusion. To our knowledge, this is the first report of long-term survival of discordant xenogeneic BM in a primate recipient.