Distinct strategies are required to suppress antigen-specific responses to genetically modified keratinocytes and fibroblasts.
Distinct strategies are required to suppress antigen-specific responses to genetically modified keratinocytes and fibroblasts.
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DOI：
10.1038/mt.2011.205
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
S. Ghazizadeh;L. Huang;Weibing Zhang
中科院分区：
文献类型：
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作者：
S. Ghazizadeh;L. Huang;Weibing Zhang
角质形成细胞和成纤维细胞是遗传性皮肤病基因/细胞治疗的潜在靶点。然而，转基因细胞的免疫消除是有效治疗的主要障碍。利用活体基因转移的方法，我们以前已经证明，两种细胞类型中的任何一种在皮肤中表达抗原都会诱导移植细胞的免疫排斥，尽管这两种细胞诱导的免疫反应的性质是不同的。在这项研究中，我们探索了局部免疫抑制策略转移转基因成纤维细胞和角质形成细胞破坏性免疫反应的有效性。抗原性成纤维细胞表达CTLA4Ig和PDL1(程度较小)，保护它们免受免疫排斥，从而导致移植物长期存活(>；18周)。类似的治疗对抗原性角质形成细胞无效。在细胞移植的前2周，通过瞬时阻断CD40/CD154的相互作用来实现对转基因角质形成细胞的长期保护。虽然这两种策略都没有诱导抗原特异性耐受，但它们足以防止转基因细胞的排斥反应。这些结果表明，即使在相同的组织中，也需要不同的策略来保护抗原细胞类型。此外，诱导抗原特异性耐受并不是转基因皮肤细胞长期生存的必要条件。
Keratinocytes and fibroblasts are potential targets of gene/cell therapy for genodermatoses. Immune elimination of genetically modified cells, however, presents a major impediment to effective therapy. Usingex vivoapproaches to gene transfer, we have previously shown that expression of an antigen by either cell type in skin induces immune rejection of transplanted cells, although the nature of immune responses induced by these two cell types are distinct. In this study, we explore the efficacy of local immunosuppressive strategies to divert destructive immune responses from genetically modified fibroblast and keratinocytes. Expression of CTLA4Ig and, to a lesser extent, PDL1, by antigenic fibroblasts protected them from immune rejection resulting in long-term graft survival (>18 weeks). Similar treatment was not effective for antigenic keratinocytes. Long-term protection of transgenic keratinocytes was achieved through transient blockade of CD40/CD154 interactions during the first 2 weeks of cell transplantation. Although neither of these strategies induced antigen-specific tolerance, they were sufficient to prevent rejection of genetically modified cells. These results indicate that different strategies are required to protect antigenic cell types even within the same tissue. Moreover, induction of antigen-specific tolerance is not a necessary requirement for long-term survival of genetically modified skin cells.