Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients
Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients
复制标题
DOI：
10.1097/tp.0b013e3182a203e4
复制
发表时间：
2013-11-27
期刊：
影响因子：
6.2
通讯作者：
Baan, Carla C.
中科院分区：
文献类型：
--
作者：
Bouvy, Anne P.;Kho, Marcia M. L.;Baan, Carla C.
背景淋巴细胞耗竭疗法与对重新增殖的T细胞的长期影响以及随后的感染和恶性肿瘤发生率增加有关。T细胞再增殖及其移植后动力学的机制尚未完全理解。我们研究了移植后前6个月兔抗胸腺细胞球蛋白（rATG）治疗患者中CD 31（+）初始T细胞（近期胸腺移出者）的胸腺生成和Ki-67（+）T细胞的稳态增殖。接受巴利昔单抗或未接受诱导治疗的患者作为对照。移植后6个月，rATG治疗组患者的T细胞数量低于移植前，而两个对照组的T细胞数量保持稳定。在此时间段内，三个治疗组之间的胸腺生成相似; CD 8（+）T细胞显示近期胸腺移出的百分比最高。在第1个月，rATG治疗患者中Ki-67（+）初始和记忆CD 4（+）和CD 8（+）T细胞的百分比最高，但这些百分比在随后的几个月内下降。当CD 31用于区分初始T细胞中的精氨酸和抗原驱动的增殖时，我们发现了精氨酸依赖性增殖的证据。细胞因子依赖性增殖还表现为体内磷酸化STAT 5百分比增加以及T细胞白细胞介素-7受体-α和白细胞介素-15受体-α的高表达水平。这些发现表明，在rATG治疗后的第一个月，精氨酸诱导的稳态增殖参与幼稚和记忆T细胞的T细胞再增殖。在稍后的时间点，稳态增殖的贡献减少，这解释了观察到的不完全T细胞恢复。
Background. Lymphocyte-depleting therapy is associated with long-lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies. The mechanisms of T-cell repopulation and their posttransplantation kinetics are not fully understood.Methods. We studied thymopoiesis by CD31(+) naive T cells (recent thymic emigrants) and homeostatic proliferation by Ki-67(+) T cells in rabbit antithymocyte globulin (rATG)-treated patients the first 6 months after transplantation. Patients receiving basiliximab or no induction therapy served as controls.Results. At 6 months after transplantation, T-cell numbers were lower than before transplantation in rATG-treated patients, whereas T-cell numbers remained stable in both control groups. In this time period, thymopoiesis was similar between the three treatment groups; CD8(+) T cells showed the highest percentage of recent thymic emigrants. At month 1, percentages of Ki-67(+) naive and memory CD4(+) and CD8(+) T cells were the highest in rATG-treated patients, but these percentages declined in the months thereafter. When CD31 was used to distinguish between cytokine-and antigen-driven proliferation in naive T cells, we found evidence for cytokine-dependent proliferation. Cytokine-dependent proliferation was also shown by in vivo increased percentages of phosphorylated STAT5 and high expression levels of the interleukin-7 receptor-alpha and interleukin-15 receptor-alpha by T cells.Conclusion. These findings demonstrate that, in the first month after rATG therapy, cytokine-induced homeostatic proliferation is involved in T-cell repopulation of both naive and memory T cells. At later time points, the contribution of homeostatic proliferation diminished, which explains the observed incomplete T-cell recovery.