We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA-FasL) on their surface survive indefinitely in allogeneic recipients without a need for chronic immunosuppression. Mechanisms that confer long-term protection to allograft are yet to be elucidated. We herein demonstrated that immune protection evolves in two distinct phases; induction and maintenance. SA-FasL-engineered allogeneic islets survived indefinitely and conferred protection to a second set of donor-matched, but not third-party, unmanipulated islet grafts simultaneously transplanted under the contralateral kidney capsule. Protection at the induction phase involved a reduction in the frequency of proliferating alloreactive T cells in the graft-draining lymph nodes, and required phagocytes and TGF-β. At the maintenance phase, immune protection evolved into graft site-restricted immune privilege as the destruction of long-surviving SA-FasL-islet grafts by streptozotocin followed by the transplantation of a second set of unmanipulated islet grafts into the same site from the donor, but not third party, resulted in indefinite survival. The induced immune privilege required both CD4+ CD25+ Foxp3+ Treg cells and persistent presence of donor antigens. Engineering cell and tissue surfaces with SA-FasL protein provides a practical, efficient, and safe means of localized immunomodulation with important implications for autoimmunity and transplantation.

中文翻译：

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用 FasL 蛋白改造的胰岛在诱导阶段诱导系统耐受，演变成长期移植物局部免疫特权。

我们之前已经表明，经改造以在其表面瞬时显示修饰形式的 FasL 蛋白 (SA-FasL) 的胰岛在同种异体受体中无限期存活，无需慢性免疫抑制。赋予同种异体移植物长期保护的机制尚未阐明。我们在此证明了免疫保护在两个不同的阶段发展；导入和维护。SA-FasL 工程化的同种异体胰岛无限期存活，并为同时移植到对侧肾囊下的第二组供体匹配但第三方未经处理的胰岛移植物提供保护。诱导期的保护涉及减少移植物引流淋巴结中同种异体反应性 T 细胞增殖的频率，并且需要吞噬细胞和 TGF-β。在维护阶段，免疫保护演变为移植部位限制性免疫特权，因为链脲佐菌素破坏了长期存活的 SA-FasL-胰岛移植物，随后将第二组未经处理的胰岛移植物从供体而非第三方移植到同一部位，导致无限期的生存。诱导的免疫特权需要 CD4+ CD25+ Foxp3+ Treg 细胞和持续存在的供体抗原。用 SA-FasL 蛋白工程化细胞和组织表面提供了一种实用、高效和安全的局部免疫调节方法，对自身免疫和移植具有重要意义。