Evaluation of the impact of conventional immunosuppressant on the establishment of murine transplantation tolerance - an experimental study
Evaluation of the impact of conventional immunosuppressant on the establishment of murine transplantation tolerance - an experimental study
复制标题
DOI：
10.1111/tri.13390
复制
发表时间：
2019-04-01
影响因子：
3.1
通讯作者：
Tanabe, Kazunari
中科院分区：
文献类型：
--
作者：
Katsumata, Haruki;Miyairi, Satoshi;Tanabe, Kazunari
调节性T细胞（Regulatory T cells，Tcells）在免疫耐受中起重要作用。由于Treg功能深深依赖于白细胞介素-2信号传导，钙调磷酸酶抑制剂可能影响其抑制潜力，而哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂可能影响较小，因为mTOR信号传导对Treg增殖不是根本性的。我们以前报道了一种新的混合造血嵌合体诱导方案，通过在CD 40阻断下刺激恒定的自然杀伤T细胞来促进Treg增殖。在这里，我们使用小鼠模型来显示他克莫司（TAC）或依维莫司（EVL）对方案中嵌合体和Treg增殖的建立的影响。在免疫抑制药物给药阶段，TAC和EVL均显著增强外周血嵌合体。停止给药后，TAC治疗的小鼠表现出逐渐的移植排斥反应，而EVL治疗的小鼠持续长期稳定的嵌合状态。TAC处理的小鼠的T细胞显示Ki 67和细胞毒性T淋巴细胞抗原-4（CTLA-4）两者的较低表达，并且体外抑制活性低于EVL处理的小鼠的T细胞，表明TAC通过干扰Treg增殖和活化而对方案产生负面影响。我们的研究结果表明，使用钙调磷酸酶抑制剂应避免使用，如果利用该方案在体内诱导T细胞的混合造血嵌合体的建立。
Regulatory T cells (Tregs) play a significant role in immune tolerance. Since Treg function deeply depends on Interleukin-2 signaling, calcineurin inhibitors could affect their suppressive potentials, whereas mammalian target of rapamycin (mTOR) inhibitors may have less impact, as mTOR signaling is not fundamental to Treg proliferation. We previously reported a novel mixed hematopoietic chimerism induction regimen that promotes Treg proliferation by stimulating invariant natural killer T cells under CD40 blockade. Here, we use a mouse model to show the impact of tacrolimus (TAC) or everolimus (EVL) on the establishment of chimerism and Treg proliferation in the regimen. In the immunosuppressive drug-dosing phase, peripheral blood chimerism was comparably enhanced by both TAC and EVL. After dosing was discontinued, TAC-treated mice showed gradual graft rejection, whereas EVL-treated mice sustained long-term robust chimerism. Tregs of TAC-treated mice showed lower expression of both Ki67 and cytotoxic T lymphocyte antigen-4 (CTLA-4), and lower suppressive activity in vitro than those of EVL-treated mice, indicating that TAC negatively impacted the regimen by interfering with Treg proliferation and activation. Our results suggest that the usage of calcineurin inhibitors should be avoided if utilizing the regimen to induce Tregs in vivo for the establishment of mixed hematopoietic chimerism.