Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients
Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients
复制标题
DOI：
10.1182/bloodadvances.2017011072
复制
发表时间：
2018-01-23
期刊：
影响因子：
7.5
通讯作者：
Oliveira, Maria Carolina
中科院分区：
文献类型：
--
作者：
Arruda, Lucas C. M.;Malmegrim, Kelen C. R.;Oliveira, Maria Carolina
为了评价自体造血干细胞移植（AHSCT）后与临床结局相关的免疫学机制，重点关注调节性T（Treg）和B（布雷格）细胞免疫重建，31例系统性硬化症（SSc）患者在移植后36个月随访期间同时接受了临床和免疫学评价。根据AHSCT后的临床应答，将患者回顾性分为应答者（n = 25）和无应答者（n = 6）。胸腺功能和B细胞新生分别通过定量T和B细胞受体重排过程中产生的DNA切除环进行评估。在对所有移植SSc患者进行AHSCT后1年评价时，胸腺反弹导致免疫系统更新，与移植前水平相比，T细胞受体（TCR）多样性更高，近期胸腺移行细胞与Treg计数呈正相关，并且TCR 4上CTLA-4和GITR的表达更高。同时，AHSCT后6个月开始，新生成的幼稚B细胞的骨髓输出增加，更新外周血中的B细胞群。在AHSCT后6个月和12个月，Bcadil增加，产生比移植前更高的白细胞介素-10水平。当对无应答患者进行单独评估时，AHSCT后Treg和布雷格计数没有增加，移植前后TCR库的高重叠表明潜在疾病机制的维持。这些数据表明，SSc患者的临床改善与AHSCT后由于协调的胸腺和骨髓反弹而导致的新生成的TcR和BcR计数增加有关。
To evaluate the immunological mechanisms associated with clinical outcomes after autologous hematopoietic stem cell transplantation (AHSCT), focusing on regulatory T- (Treg) and B- (Breg) cell immune reconstitution, 31 systemic sclerosis (SSc) patients underwent simultaneous clinical and immunological evaluations over 36-month posttransplantation follow-up. Patients were retrospectively grouped into responders (n = 25) and nonresponders (n = 6), according to clinical response after AHSCT. Thymic function and B-cell neogenesis were respectively assessed by quantification of DNA excision circles generated during T- and B-cell receptor rearrangements. At the 1-year post-AHSCT evaluation of the total set of transplanted SSc patients, thymic rebound led to renewal of the immune system, with higher T-cell receptor (TCR) diversity, positive correlation between recent thymic emigrant and Treg counts, and higher expression of CTLA-4 and GITR on Tregs, when compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre- and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.