Division of Plastic Surgery, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA.
Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Transplantation. 2018 Jan;102(1):70-78. doi: 10.1097/TP.0000000000001852.
Vascularized composite allografts (VCA) are novel, life-enhancing forms of transplantation (Tx). However, host immune responses to the various VCA components, especially those involving skin, are complex and make selection of appropriate therapy challenging. Although the interplay between Foxp3+ T regulatory (Treg) cells and CD4 and CD8 effector T cells is of central importance in determining the acceptance or rejection of solid organ allografts, there is little information available concerning the contribution of Treg cells to VCA survival. In addition, the effects of therapeutic expansion in vivo of host Treg cell populations on VCA survival are unknown.
We established a fully major histocompatibility complex-disparate (BALB/c- > C57BL/6) murine orthotopic forelimb Tx model to explore the benefits of pre- and post-Tx IL-2/anti-IL-2 monoclonal antibody complex (IL-2C) administration to expand the host Treg cell population and thereby attempt to promote Treg cell-dependent VCA survival.
Both strategies expanded the Treg cell population in vivo and prolonged VCA survival (P < 0.001), but IL-2C administration pre-Tx led to significantly longer survival compared with IL-2C administration post-Tx (P < 0.01). In addition, compared with post-Tx therapy, pre-Tx therapy resulted in an increased ratio of Treg cells to CD8+ T cells (P < 0.001), reduced proliferation of CD4 and CD8 effector T cells, and reduced production of IFN-γ. Optimal effects were seen when combined with rapamycin therapy, whereas the combination of IL-2C therapy plus calcineurin inhibitor was counterproductive.
Our studies involving different IL-2C-mediated Treg cell expansion strategies demonstrate that pre-Tx IL-2C therapy may be a useful component for developing strategies to promote VCA survival.
血管化复合组织同种异体移植物（VCA）是一种新颖的、提高生活质量的移植形式。然而，宿主对各种 VCA 成分的免疫反应，特别是涉及皮肤的反应，是复杂的，这使得选择合适的治疗方法具有挑战性。尽管 Foxp3+T 调节（Treg）细胞与 CD4 和 CD8 效应 T 细胞之间的相互作用对于确定实体器官同种异体移植物的接受或排斥至关重要，但关于 Treg 细胞对 VCA 存活的贡献，信息很少。此外，宿主 Treg 细胞群体在体内治疗性扩增对 VCA 存活的影响尚不清楚。
我们建立了一个完全主要组织相容性复合物不同的（BALB/c- > C57BL/6）小鼠原位前肢 Tx 模型，以探讨在 Tx 前和 Tx 后给予 IL-2/抗 IL-2 单克隆抗体复合物（IL-2C）以扩增宿主 Treg 细胞群体，从而尝试促进 Treg 细胞依赖的 VCA 存活的益处。
两种策略都在体内扩增了 Treg 细胞群体，并延长了 VCA 的存活时间（P < 0.001），但 Tx 前给予 IL-2C 比 Tx 后给予 IL-2C 导致更长的存活时间（P < 0.01）。此外，与 Tx 后治疗相比，Tx 前治疗导致 Treg 细胞与 CD8+T 细胞的比例增加（P < 0.001），CD4 和 CD8 效应 T 细胞的增殖减少，IFN-γ 的产生减少。与雷帕霉素联合治疗效果最佳，而 IL-2C 联合钙调神经磷酸酶抑制剂治疗则适得其反。
我们涉及不同 IL-2C 介导的 Treg 细胞扩增策略的研究表明，Tx 前 IL-2C 治疗可能是促进 VCA 存活的策略的有用组成部分。
