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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts
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Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts

机译：免疫抑制疗法可减轻人类胚胎干细胞异种移植的免疫排斥反应

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摘要

Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immuno-deficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4~+ T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.
机译：考虑到它们的自我更新和多能性，人类胚胎干细胞（hESCs）有望成为组织再生治疗的细胞来源。但是，宿主对移植的hESC的免疫反应尚未很好地表征。实际上，关于人类胚胎干细胞是否具有免疫特权的特性仍存在争议。为了解决这个问题，我们使用体内生物发光成像技术来追踪由萤火虫荧光素酶和增强型GFP组成的双融合报告基因稳定转导的已移植hESC的命运。我们表明，与免疫缺陷小鼠相比，移植后的存活率在免疫能力方面受到明显限制。将hESC重复移植到具有免疫能力的宿主中会导致hESC死亡加速，表明有适应性的供体特异性免疫应答。我们的数据表明，移植的hESC触发强大的细胞和体液免疫反应，导致炎症细胞的移植物内浸润和随后的hESC排斥。此外，我们发现CD4〜+ T细胞是hESC免疫介导排斥反应的重要调节剂。最后，我们表明免疫抑制药物方案可以减轻抗hESC的免疫反应，并且他克莫司和西罗莫司联合疗法的方案可显着延长hESC的存活长达28天。综上所述，这些数据表明，hESC具有免疫原性，同时触发细胞和体液介导的途径，因此在异种宿主中被迅速排斥。可以通过分子成像方法评估的联合免疫抑制方案减轻这一过程。

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