Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines -: toward tolerance induction across discordant xenogeneic barriers
Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines -: toward tolerance induction across discordant xenogeneic barriers
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DOI：
10.1097/00007890-200006270-00005
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发表时间：
2000-06-27
期刊：
影响因子：
6.2
通讯作者：
Yang, YG
中科院分区：
文献类型：
--
作者：
Chen, AM;Zhou, Y;Yang, YG
背景混合造血嵌合体是诱导耐受的可靠方法，但由于难以实现持久的造血植入，其效用尚未在不一致的异种组合中得到证实。小型猪可能是人类合适的器官供体。为了评估混合嵌合体在广泛不同的异种受体中诱导猪特异性耐受的能力，本研究旨在在猪与小鼠组合中实现持久的嵌合体。通过将携带猪白细胞介素-3、粒细胞巨噬细胞集落刺激因子和干细胞因子基因的转基因建立者与严重联合免疫缺陷小鼠或非肥胖糖尿病/严重联合免疫缺陷小鼠杂交来开发免疫缺陷转基因小鼠。对这些小鼠进行了猪骨髓移植，并对猪嵌合体进行了20周的随访。尽管猪细胞在7周时在所有非Tg同窝小鼠中变得不可检测，但高水平的猪造血嵌合体，包括宿主胸腺中猪II类+细胞的存在，在Tg小鼠中维持>20周。骨髓移植后20周，集落形成实验显示小鼠骨髓中存在大量的猪造血祖细胞。这些转基因小鼠首次证明了骨髓供体抗原呈递细胞可以自发迁移到完整的受体胸腺，并且猪干细胞可以在这种高度不同的物种组合中持续存在。因此，这些数据支持通过不一致异种组合中的混合嵌合体诱导耐受性的最终目标的可行性。
Background. Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination.Methods. Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic /severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks.Results. Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation.Conclusions. These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations.