Transplant Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Maryland, USA.
Transplant Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Maryland, USA; Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Maryland, USA.
Am J Transplant. 2023 Apr;23(4):549-558. doi: 10.1016/j.ajt.2023.01.016. Epub 2023 Feb 4.
Face transplantation is a life-changing procedure for patients with severe composite facial defects. However, it is hampered by high acute rejection rates due to the immunogenicity of skin allograft and toxicity linked to high doses of immunosuppression. To reduce immunosuppression-associated complications, we, for the first time in face transplant recipients, used low-dose interleukin 2 (IL-2) therapy to expand regulatory T cells (Tregs) in vivo and to enhance immune modulation, under close immunological monitoring of peripheral blood and skin allograft. Low-dose IL-2 achieved a sustained expansion (∼4-fold to 5-fold) of circulating Tregs and a reduction (∼3.5-fold) of B cells. Post-IL-2 Tregs exhibited greater suppressive function, characterized by higher expression of TIM-3 and LAG3co-inhibitory molecules. In the skin allograft, Tregs increased after low-dose IL-2 therapy. IL-2 induced a distinct molecular signature in the allograft with reduced cytotoxicity-associated genes (granzyme B and perforin). Two complications were observed during the trial: one rejection event and an episode of autoimmune hemolytic anemia. In summary, this initial experience demonstrated that low-dose IL-2 therapy was not only able to promote immune regulation in face transplant recipients but also highlighted challenges related to its narrow therapeutic window. More specific targeted Treg expansion strategies are needed to translate this approach to the clinic.
面部移植是治疗严重复合性面部缺陷患者的一种改变生活的手术。然而，由于皮肤移植物的免疫原性和高剂量免疫抑制带来的毒性，导致急性排斥反应率很高，从而阻碍了其发展。为了减少与免疫抑制相关的并发症，我们首次在面部移植受者中使用低剂量白细胞介素 2（IL-2）治疗，通过对患者外周血和皮肤移植物进行密切的免疫监测，在体内扩增调节性 T 细胞（Tregs）并增强免疫调节。低剂量 IL-2 实现了循环 Tregs 的持续扩增（约 4 到 5 倍）和 B 细胞的减少（约 3.5 倍）。IL-2 后 Tregs 表现出更强的抑制功能，其特征是 TIM-3 和 LAG3 共抑制分子的表达更高。在皮肤移植物中，Tregs 在低剂量 IL-2 治疗后增加。IL-2 在移植物中诱导了一个独特的分子特征，减少了细胞毒性相关基因（颗粒酶 B 和穿孔素）的表达。在试验过程中观察到了两个并发症：一次排斥反应事件和一次自身免疫性溶血性贫血。总之，这一初步经验表明，低剂量 IL-2 治疗不仅能够促进面部移植受者的免疫调节，而且还突出了与该治疗窗口狭窄相关的挑战。需要更具体的靶向 Treg 扩增策略将这种方法转化为临床实践。
