Akbar A N, Fitzgerald-Bocarsly P A, Giardina P J, Hilgartner M W, Grady R W
Department of Pediatrics, Cornell University Medical Center, New York, NY 10021.
Clin Exp Immunol. 1987 Nov;70(2):345-53.
We previously observed that natural killer (NK) activity toward K562 cells is markedly depressed in patients with beta-thalassaemia major. Here we report that these patients also exhibit significantly decreased (P less than 0.005) NK cytotoxicity against human fibroblasts infected with herpes simplex virus-type 1 (HSV-1) and that the amount of alpha-interferon (alpha-IFN) generated during the latter assays is significantly less than normal (P less than 0.005). This decreased production of alpha-IFN may account in part for the decreased NK activity seen in the thalassaemia patients. On the other hand, the cytotoxicity of their mononuclear cells (MNC) toward both K562 cells and HSV-1-infected fibroblasts could be augmented to the same extent as that of normal MNC by preincubation with alpha-IFN suggesting that thalassaemia MNC are capable of responding to this lymphokine despite their reduced ability to produce it. Moreover, preincubation of thalassaemia MNC with desferrioxamine (DFO), an iron-chelating agent, consistently increased the lysis of K562 cells indicating that the transfusion-induced iron overload which these patients experience may also contribute to the defective NK function seen in this disease. We have now found that preincubation of such MNC with DFO has no effect upon production of alpha-IFN when the MNC are cocultured with either HSV-1-infected fibroblasts or K562 cells. Combining DFO and alpha-IFN resulted in an increase in the NK activity of both normal and thalassaemia MNC against the two targets which was greater than that with alpha-IFN alone. In fact, preincubation of thalassaemia cells with this combination increased their NK activity toward K562 targets to that of untreated normal cells. This was true when either unfractionated MNC or NK-enriched fractions were used as effector cells. These results suggest that DFO and alpha-IFN enhance NK activity by different mechanisms, both of which appear to be reversibly impaired in thalassaemia patients.
我们先前观察到，重型β地中海贫血患者对K562细胞的自然杀伤（NK）活性显著降低。在此我们报告，这些患者对感染1型单纯疱疹病毒（HSV-1）的人成纤维细胞的NK细胞毒性也显著降低（P<0.005），并且在后一种检测中产生的α干扰素（α-IFN）量明显低于正常水平（P<0.005）。α-IFN产生的减少可能部分解释了地中海贫血患者中观察到的NK活性降低。另一方面，通过与α-IFN预孵育，他们的单核细胞（MNC）对K562细胞和HSV-1感染的成纤维细胞的细胞毒性可以增强到与正常MNC相同的程度，这表明地中海贫血MNC尽管产生α-IFN的能力降低，但仍能够对这种淋巴因子作出反应。此外，用铁螯合剂去铁胺（DFO）对地中海贫血MNC进行预孵育，持续增加了K562细胞的裂解，表明这些患者经历的输血诱导的铁过载也可能导致该疾病中出现的NK功能缺陷。我们现在发现，当MNC与HSV-1感染的成纤维细胞或K562细胞共培养时，用DFO对这种MNC进行预孵育对α-IFN的产生没有影响。将DFO和α-IFN联合使用导致正常和地中海贫血MNC对两个靶标的NK活性增加，且大于单独使用α-IFN时的增加幅度。事实上，用这种组合对地中海贫血细胞进行预孵育，可使其对K562靶标的NK活性增加到未处理的正常细胞的水平。当使用未分级的MNC或NK富集组分作为效应细胞时都是如此。这些结果表明，DFO和α-IFN通过不同机制增强NK活性，这两种机制在地中海贫血患者中似乎都受到可逆性损害。
