Borchers S, Luther S, Lips U, Hahn N, Kontsendorn J, Stadler M, Buchholz S, Diedrich H, Eder M, Koehl U, Ganser A, Mischak-Weissinger E
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Transpl Infect Dis. 2011 Jun;13(3):222-36. doi: 10.1111/j.1399-3062.2011.00626.x. Epub 2011 May 18.
Reactivation of cytomegalovirus (CMV) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). In healthy individuals, virus-specific T cells (CMV-CTL) control the reactivation of latent CMV. The monitoring of virus-epitope-binding CD8(+) T cells using major histocompatibility complex-I-peptide complexes (tetramers) has recently been established, allowing assessment of the reconstitution of CMV-CTL post HSCT.
In order to study immune reconstitution and reactivation control through CMV-CTL, we regularly monitored all patients undergoing allogeneic HSCT in our department for 2 years, who matched at least 1 of 6 commercially available tetramers for common human leukocyte antigen (HLA) types. To verify risk factors for CMV reactivations in our cohorts, clinical characteristics of all patients transplanted within the last 10 years were included in statistical analyses determining the relative risk for single and recurrent CMV reactivations.
As expected, CMV serostatus, HLA match, and donor source significantly influenced the risk of recurrent CMV reactivation. Applying CMV-CTL tetramer monitoring for 2 years allowed the monitoring of 114 (85%) of 134 patients, by testing a set of tetramers representing 6 epitopes from 3 different CMV proteins. The presence of CMV-CTL before day + 50 and their expansion post reactivation seem to protect against recurrent CMV reactivations. The mean number of CMV-CTL by day +100 was >5-fold higher in the recipient CMV-positive/donor-positive (R +/D +) group (91/μL) compared with the R +/ D- (13/μL) and the R -/D +(2/μL) group. Seventy-nine percent of patients from the R +/D + setting recovered >10 CMV-CTL per μL by day + 100, while almost 50% of the other groups failed to mount a CMV-specific response by that time (R +/D -: 58%; R -/D +: 43%).
Tetramer monitoring can help to predict (recurrent) CMV reactivation and is a useful approach to monitor individual patients with increased risk for recurrent reactivation post HSCT; thus, it could help to identify patients in need of adoptive transfer of CMV-CTL or to optimize the use of antiviral drugs.
巨细胞病毒（CMV）再激活是异基因造血干细胞移植（HSCT）后发病的主要原因。在健康个体中，病毒特异性T细胞（CMV-CTL）可控制潜伏CMV的再激活。最近已建立使用主要组织相容性复合体-I-肽复合物（四聚体）监测病毒表位结合CD8(+) T细胞的方法，从而能够评估HSCT后CMV-CTL的重建情况。
为了通过CMV-CTL研究免疫重建和再激活控制，我们对本部门接受异基因HSCT的所有患者进行了为期2年的定期监测，这些患者与6种市售四聚体中至少1种常见人类白细胞抗原（HLA）类型相匹配。为了验证我们队列中CMV再激活的危险因素，将过去10年内所有移植患者的临床特征纳入统计分析，以确定单次和复发性CMV再激活的相对风险。
正如预期的那样，CMV血清状态、HLA匹配和供体来源显著影响复发性CMV再激活的风险。通过检测一组代表来自3种不同CMV蛋白的6个表位的四聚体，应用CMV-CTL四聚体监测2年可对134例患者中的114例（85%）进行监测。移植后第50天之前存在CMV-CTL以及其在再激活后的扩增似乎可预防复发性CMV再激活。与受体CMV阳性/供体阴性（R +/D -）组（13/μL）和受体CMV阴性/供体阳性（R -/D +）组（2/μL）相比，受体CMV阳性/供体阳性（R +/D +）组移植后第100天CMV-CTL的平均数量高出5倍多（91/μL）。R +/D +组中79%的患者在移植后第100天每微升恢复>10个CMV-CTL，而其他组中近50%的患者在此时未能产生CMV特异性反应（R +/D -组：58%；R -/D +组：43%）。
四聚体监测有助于预测（复发性）CMV再激活，是监测HSCT后复发性再激活风险增加的个体患者的有用方法；因此，它有助于识别需要过继转移CMV-CTL的患者或优化抗病毒药物的使用。
