Hakim F T, Cepeda R, Kaimei S, Mackall C L, McAtee N, Zujewski J, Cowan K, Gress R E
Medicine Branch and Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blood. 1997 Nov 1;90(9):3789-98.
To examine the mechanisms of CD4 reconstitution in an adult population, lymphocyte repopulation was assessed following dose-intense chemotherapy in 25 breast cancer patients, ages 33 to 69 years. Chemotherapy resulted in a greater than 60% reduction in total CD4 T cells and, in particular, a greater than 90% loss of the CD45RA+ CD4 cells. CD4 recovery was protracted, achieving less than 50% of pretreatment levels after 12 to 14 months. Two facets of the CD4 recovery were notable. First, generation of CD45RA+ CD4 cells played only a minor role in the first year, suggesting that thymic production was not the main route of CD4 regeneration. Indeed, recovery of CD45RA+ CD4 cell levels remained limited in half of the patients even after 2 years. Second, expansion of the mature peripheral CD4 cells (CD45RO+) remaining after chemotherapy was the main source of early CD4 repopulation, peaking at 3 to 6 months postchemotherapy. This expansion was limited in duration, however, and was followed by a secondary decline, such that the total CD45RO+ CD4 levels at 9 to 12 months were lower than at 6 months. When stimulated by mitogens, an increased susceptibility to apoptosis was observed in postchemotherapy CD4 cells as compared with those from normal donors. The elevated expression of markers such as HLA-DR during chemotherapy and for several months postchemotherapy is consistent with the presence of an activated T-cell population. CD4 apoptotic frequency correlated with the frequency of HLA-DR expression on T cells. Thus, CD4 recovery is constrained in adults by a limited thymic regenerative capacity and by an increased susceptibility to apoptosis within the expanding peripheral CD4 population.
为研究成年人群中CD4重建的机制，对25例年龄在33至69岁的乳腺癌患者进行了剂量密集化疗后的淋巴细胞再增殖评估。化疗导致总CD4 T细胞减少超过60%，特别是CD45RA+ CD4细胞损失超过90%。CD4恢复过程漫长，12至14个月后仍未达到预处理水平的50%。CD4恢复的两个方面值得注意。首先，CD45RA+ CD4细胞的生成在第一年仅起次要作用，这表明胸腺产生并非CD4再生的主要途径。事实上，即使在2年后，仍有一半患者的CD45RA+ CD4细胞水平恢复有限。其次，化疗后残留的成熟外周CD4细胞（CD45RO+）的扩增是早期CD4再增殖的主要来源，在化疗后3至6个月达到峰值。然而，这种扩增持续时间有限，随后出现二次下降，使得9至12个月时的总CD45RO+ CD4水平低于6个月时。与正常供体的CD4细胞相比，化疗后的CD4细胞在受到丝裂原刺激时对凋亡的敏感性增加。化疗期间及化疗后数月，HLA-DR等标志物表达升高，这与活化T细胞群体的存在一致。CD4凋亡频率与T细胞上HLA-DR表达频率相关。因此，成年人的CD4恢复受到胸腺再生能力有限以及外周CD4细胞扩增过程中凋亡敏感性增加的限制。
