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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance
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Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance

机译：胚胎干细胞来源的组织具有免疫原性，但其固有的免疫特权可促进耐受性的诱导

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Although human embryonic stem (ES) cells may one day provide a renewable source of tissues for cell replacement therapy (CRT), histoincompatibility remains a significant barrier to their clinical application. Current estimates suggest that surprisingly few cell lines may be required to facilitate rudimentary tissue matching. Nevertheless, the degree of disparity between donor and recipient that may prove acceptable, and the extent of matching that is therefore required, remain unknown. To address this issue using a mouse model of CRT, we have derived a panel of ES cell lines that differ from CBA/Ca recipients at defined genetic loci. Here, we show that even expression of minor histocompatibility (mH) antigens is sufficient to provoke acute rejection of tissues differentiated from ES cells. Nevertheless, despite their immunogenicity in vivo, transplantation tolerance may be readily established by using minimal host conditioning with nondepleting monoclonal antibodies specific for the T cell coreceptors, CD4 and CD8. This propensity for tolerance could be attributed to the paucity of professional antigen-presenting cells and the expression of transforming growth factor (TGF)-β_2. Together, these factors contribute to a state of acquired immune privilege that favors the polarization of infiltrating T cells toward a regulatory phenotype. Although the natural privileged status of ES cell-derived tissues is, therefore, insufficient to overcome even mH barriers, our findings suggest it may be harnessed effectively for the induction of dominant tolerance with minimal therapeutic intervention.
机译：尽管人类胚胎干（ES）细胞有一天可能为细胞替代治疗（CRT）提供组织的可再生来源，但组织相容性仍然是其临床应用的重要障碍。当前的估计表明出乎意料地需要很少的细胞系来促进基本的组织匹配。然而，捐赠者和接受者之间的差异程度可能被证明是可以接受的，因此需要的匹配程度仍然未知。为了使用CRT小鼠模型解决此问题，我们衍生了一组ES细胞系，它们与定义的基因座处的CBA / Ca受体不同。在这里，我们表明，即使是次要组织相容性（mH）抗原的表达也足以引起从ES细胞分化的组织的急性排斥反应。尽管如此，尽管它们具有体内免疫原性，但可以通过使用最少的宿主条件和对T细胞共受体CD4和CD8特异的非消耗性单克隆抗体来轻易建立移植耐受性。这种耐受性的倾向可以归因于专业抗原呈递细胞的缺乏和转化生长因子（TGF）-β_2的表达。这些因素共同构成了获得性免疫特权的状态，有利于浸润性T细胞向调节表型的极化。因此，尽管ES细胞源性组织的天然特权地位不足以克服mH障碍，但我们的发现表明，可以通过最少的治疗干预有效地利用它来诱导显性耐受。

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