Kreijveld Ellen, Koenen Hans J P M, van Cranenbroek Bram, van Rijssen Esther, Joosten Irma, Hilbrands Luuk B
Department of Blood Transfusion and Transplantation Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS One. 2008 Jul 16;3(7):e2711. doi: 10.1371/journal.pone.0002711.
Transplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal.
Prior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors.
Immunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced.
如果能预防移植排斥反应，移植患者将从免疫抑制的减少中获益。我们评估了肾移植后停用他克莫司的患者血液中的多种免疫标志物。在移植前和减少他克莫司剂量前，分析了CD4+和CD8+ T细胞的同种异体反应性前体细胞频率、T细胞亚群频率以及CD4+CD25+FoxP3+调节性T细胞（Treg）的功能能力。在病例对照设计中，比较了停用他克莫司后发生（n = 15）和未发生（n = 28）急性排斥反应的患者的结果。
在减少他克莫司剂量之前，与未发生排斥反应的患者相比，发生排斥反应的患者中记忆性CD8+ T细胞与Treg的比例更高。发生排斥反应的患者中记忆性CD4+ T细胞与Treg的比例也更高，且比例<20仅在未发生排斥反应的患者中观察到。在移植时到开始停用他克莫司之间，发生排斥反应的患者中幼稚T细胞频率增加，效应T细胞百分比相应下降。移植后CD4+ T细胞中Treg的比例下降，但Treg的抗供体调节能力在发生排斥反应和未发生排斥反应的患者中均保持不变。
免疫监测显示，停用他克莫司后的急性排斥反应与1）开始减少他克莫司剂量前记忆性T细胞与Treg的比例，以及2）幼稚、效应和记忆性T细胞随时间的分布变化之间存在关联。这两种生物标志物的组合能够高度特异性地识别可以安全减少免疫抑制的患者。
