Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Transpl Int. 2011 Sep;24(9):920-31. doi: 10.1111/j.1432-2277.2011.01285.x. Epub 2011 Jun 14.
Antiviral prophylaxis has proved successful for prevention of cytomegalovirus (CMV) disease in solid organ transplant (SOT) patients; though emerging data suggest that antiviral agents interfere with immunity, and may inhibit immune priming. In this context, we investigated levels and phenotype of primary CMV-specific immune responses that developed during antiviral prophylaxis in a cohort of CMV seronegative recipients (R(-) ) of a SOT from a seropositive donor (D(+) ). We longitudinally monitored CMV viral load, antibodies and levels of the negative immuno-modulator IL-10. PBMC were stimulated with CMV-specific peptide libraries to measure CD137 activation marker on CMV-specific T-cells and levels of PD-1 receptor, which is over expressed on exhausted T-cells. Unexpectedly, the majority (13/18) of D(+) R(-) patients who developed a primary CMV response showed early post-transplant CMV-specific responses, though levels of PD-1 on CMV-specific T-cells remained elevated throughout prophylaxis. A strong inverse association was found between levels of plasma IL-10 and CMV-specific cellular immune responses. Our study suggests that during prophylaxis, subclinical CMV infection might have occurred in the D(+) R(-) patients, and primary CMV-specific responses were detected early post-transplant when levels of plasma IL-10 were low. Extended prophylaxis or antiviral treatment did not appear to suppress CMV-specific antibodies or T-cells, which, however, showed exhaustion phenotypes.
抗病毒预防已被证明可成功预防实体器官移植 (SOT) 患者的巨细胞病毒 (CMV) 疾病；尽管新出现的数据表明抗病毒药物会干扰免疫，并可能抑制免疫启动。在这种情况下，我们在来自 CMV 阳性供体（D(+)）的 SOT 的 CMV 血清阴性受者（R(-)）队列中研究了在抗病毒预防期间发展的原发性 CMV 特异性免疫反应的水平和表型。我们纵向监测 CMV 病毒载量、抗体和负免疫调节剂 IL-10 的水平。用 CMV 特异性肽文库刺激 PBMC 以测量 CMV 特异性 T 细胞上的 CD137 激活标记物和 PD-1 受体的水平，PD-1 受体在耗尽的 T 细胞上过度表达。出乎意料的是，尽管在整个预防期间，PD-1 特异性 T 细胞上的 PD-1 水平仍然升高，但大多数（13/18）发生原发性 CMV 反应的 D(+) R(-) 患者在移植后早期出现了 CMV 特异性反应。我们发现，血浆 IL-10 水平与 CMV 特异性细胞免疫反应之间存在强烈的负相关。我们的研究表明，在预防期间，D(+) R(-) 患者可能发生了亚临床 CMV 感染，并且在血浆 IL-10 水平较低时，在移植后早期检测到原发性 CMV 特异性反应。延长预防或抗病毒治疗似乎并没有抑制 CMV 特异性抗体或 T 细胞，然而，这些细胞表现出衰竭表型。
