Transplantation Research Institute, Seoul National University College of Medicine, Republic of Korea.
Transpl Immunol. 2013 Mar;28(2-3):86-92. doi: 10.1016/j.trim.2013.01.005. Epub 2013 Jan 26.
Retransplantation is common in allogeneic islet transplantation, and therefore, memory responses in previously sensitized recipients present a distinct obstacle for successful islet transplantation. Given the difficulties in controlling memory responses contributing to allograft rejection, it is worth investigating the effects of new immune-modulating agents against islet allograft rejection in the sensitized recipients. In this study, we investigated immune-modulating agents including 5-azacytidine and IL-2/anti-IL-2 complex to ascertain their suppressive effects on memory responses. In suppression assays, rapamycin effectively suppressed the proliferation of memory T cells, whereas 5-azacytidine, a methylation inhibitor suppressed the survival and proliferation of memory T cells. Combination therapy of anti-CD40L, anti-OX40L, and rapamycin slightly prolonged BALB/c islet allograft survival in sensitized C57BL6 mice, and reduced intragraft infiltration of macrophages, T cells, and B cells. However, the addition of IL-2/anti-IL-2 complex, an inducer of regulatory T cells, did not exhibit additional suppression against rejection in sensitized mice. Although a combination of 5-azacytidine and rapamycin markedly suppressed islet allograft rejection in naïve mice, it failed to achieve long-term graft survival even when combined with anti-CD40L and anti-OX40 in sensitized mice. In short, 5-azacytidine-based or IL-2/anti-IL-2 complex-based regimens can suppress islet allograft rejection in naïve recipients, but fail to control islet allograft rejection in sensitized recipients.
同种异体胰岛移植中常进行再移植，因此，先前致敏受者中的记忆反应对成功的胰岛移植构成了明显的障碍。鉴于控制导致同种异体移植物排斥的记忆反应存在困难，因此值得研究新的免疫调节药物在致敏受者中对胰岛同种异体移植排斥的作用。在这项研究中，我们研究了免疫调节药物，包括 5-氮杂胞苷和 IL-2/抗 IL-2 复合物，以确定它们对记忆反应的抑制作用。在抑制实验中，雷帕霉素有效抑制了记忆 T 细胞的增殖，而 5-氮杂胞苷作为一种甲基化抑制剂，抑制了记忆 T 细胞的存活和增殖。抗 CD40L、抗 OX40L 和雷帕霉素的联合治疗在致敏 C57BL6 小鼠中略微延长了 BALB/c 胰岛同种异体移植物的存活时间，并减少了移植物内巨噬细胞、T 细胞和 B 细胞的浸润。然而，添加 IL-2/抗 IL-2 复合物，一种调节性 T 细胞的诱导剂，并没有在致敏小鼠中表现出对排斥反应的额外抑制作用。尽管 5-氮杂胞苷和雷帕霉素的联合治疗显著抑制了新生小鼠的胰岛同种异体移植排斥反应，但即使与致敏小鼠中的抗 CD40L 和抗 OX40 联合使用，也未能实现长期移植物存活。总之，基于 5-氮杂胞苷的或基于 IL-2/抗 IL-2 复合物的方案可以抑制新生受者的胰岛同种异体移植排斥反应，但不能控制致敏受者的胰岛同种异体移植排斥反应。
