The Rotterdam Transplant Group, Erasmus MC, Department of Internal Medicine, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Transplantation. 2019 Oct;103(10):2065-2074. doi: 10.1097/TP.0000000000002773.
Interleukin 21 (IL-21) is involved in regulating the expansion and effector function of a broad range of leukocytes, including T cells and B cells. In transplantation, the exact role of IL-21 in the process of allograft rejection is unknown. To further explore this, the aim of this study is to test the effect of an IL-21 receptor (IL-21R) blocking antibody on the early phase of allograft rejection in a humanized skin transplantation model in mice reconstituted with human T and B cells.
Immunodeficient Balb/c IL2rγRag2 mice were transplanted with human skin followed by adoptive transfer of human allogeneic splenocytes. Control animals were treated with a phosphate buffered saline vehicle while the other group was treated with a humanized anti-IL-21R antibody (αIL-21R).
In the phosphate buffered saline-treated animals, human skin allografts were infiltrated with lymphocytes and developed a thickened epidermis with increased expression of the inflammatory markers Keratin 17 (Ker17) and Ki67. In mice treated with αIL-21R, these signs of allograft reactivity were significantly reduced. Concordantly, STAT3 phosphorylation was inhibited in this group. Of note, treatment with αIL-21R attenuated the process of T and B cell reconstitution after adoptive cellular transfer.
These findings demonstrate that blockade of IL-21 signaling can delay allograft rejection in a humanized skin transplantation model.
白细胞介素 21（IL-21）参与调节多种白细胞（包括 T 细胞和 B 细胞）的扩增和效应功能。在移植中，IL-21 在同种异体移植物排斥过程中的确切作用尚不清楚。为了进一步探讨这一点，本研究旨在测试 IL-21 受体（IL-21R）阻断抗体在用人 T 和 B 细胞重建的小鼠人源化皮肤移植模型中对同种异体移植物排斥早期阶段的影响。
免疫缺陷 Balb/c IL2rγRag2 小鼠接受人皮肤移植，随后进行同种异体脾细胞过继转移。对照组用磷酸盐缓冲盐水（PBS）处理，而另一组用抗人 IL-21R 抗体（αIL-21R）处理。
在 PBS 处理的动物中，人皮肤移植物被淋巴细胞浸润，并出现表皮增厚，炎症标志物角蛋白 17（Ker17）和 Ki67 的表达增加。在接受αIL-21R 治疗的小鼠中，这些同种异体反应的迹象明显减少。相应地，该组中 STAT3 磷酸化受到抑制。值得注意的是，αIL-21R 治疗减弱了过继细胞转移后 T 和 B 细胞重建的过程。
这些发现表明，阻断 IL-21 信号可以延迟人源化皮肤移植模型中的同种异体移植物排斥。
