Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients.
Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients.
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发表时间：
2001-06
期刊：
影响因子：
11.2
通讯作者：
J. Schmielau;O. Finn
中科院分区：
文献类型：
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作者：
J. Schmielau;O. Finn
晚期癌症患者的T细胞功能受损已被广泛认可，但迄今为止报道的机制主要是在肿瘤微环境中运作的机制。很少有机制被提出来解释外周血T细胞中几种被充分描述的缺陷，如信号分子表达减少，细胞因子产生减少或细胞凋亡增加。我们仔细检查了来自患者和健康个体的外周血单核细胞（PBMC）样本，我们观察到了一个重要的差异，这可能是大多数报告的缺陷的基础。我们观察到，仅在来自患者的样品中，异常大量的粒细胞与低密度PBMC在密度梯度上共纯化，而不是如预期的那样沉积到梯度的底部。我们还表明，用N-甲酰基-L-甲硫氨酰-L-亮氨酰-L-苯丙氨酸激活来自健康供体的粒细胞也可能导致它们异常沉积并与PBMC共纯化，这表明密度变化是它们激活的标志。为了证实这一点，我们寻找体内粒细胞活化的其他证据，并发现它在急剧升高的血浆水平的8-异前列腺素，脂质过氧化的产物和氧化应激的标志物。患者T细胞的T细胞受体ζ链表达减少和细胞因子产生减少与其PBMC中存在活化粒细胞相关。我们发现，从健康供体新鲜获得的粒细胞，如果激活，也可以抑制T细胞产生细胞因子。加入过氧化氢（H（2）O（2））清除剂过氧化氢酶后，这种作用被消除，表明H（2）O（2）是效应分子。事实上，当单独加入时，H2 O 2可以抑制正常T细胞的细胞因子产生。这些发现表明，粒细胞在晚期癌症患者中被激活，粒细胞来源的H（2）O（2）是严重的系统性T细胞抑制的主要原因。
Impaired T-cell function in patients with advanced cancer has been a widely acknowledged finding, but mechanisms reported thus far are those primarily operating in the tumor microenvironment. Very few mechanisms have been put forth to explain several well-described defects in peripheral blood T cells, such as reduction in expression of signaling molecules, decreased production of cytokines, or increased apoptosis. We have closely examined the peripheral blood mononuclear cell (PBMC) samples derived from patients and healthy individuals, and we have observed an important difference that may underlie the majority of reported defects. We observed that in samples from patients only, an unusually large number of granulocytes copurify with low density PBMCs on a density gradient rather than sediment, as expected, to the bottom of the gradient. We also show that activating granulocytes from a healthy donor with N-formyl-L-methionyl-L-leucyl-L-phenylalanine could also cause them to sediment aberrantly and copurify with PBMCs, suggesting that density change is a marker of their activation. To confirm this, we looked for other evidence of in vivo granulocyte activation and found it in drastically elevated plasma levels of 8-isoprostane, a product of lipid peroxidation and a marker of oxidative stress. Reduced T-cell receptor zeta chain expression and decreased cytokine production by patients' T cells correlated with the presence of activated granulocytes in their PBMCs. We showed that freshly obtained granulocytes from healthy donors, if activated, can also inhibit cytokine production by T cells. This action is abrogated by the addition of the hydrogen peroxide (H(2)O(2)) scavenger, catalase, implicating H(2)O(2) as the effector molecule. Indeed, when added alone, H(2)O(2) could suppress cytokine production of normal T cells. These findings indicate that granulocytes are activated in advanced cancer patients and that granulocyte-derived H(2)O(2) is the major cause of severe systemic T-cell suppression.