Continuous stress disrupts immunostimulatory effects of IL-12.
Continuous stress disrupts immunostimulatory effects of IL-12.
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DOI：
10.1016/j.bbi.2011.01.014
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发表时间：
2011-05
影响因子：
15.1
通讯作者：
Ben-Eliyahu, Shamgar
中科院分区：
文献类型：
--
作者：
Levi, Ben;Benish, Marganit;Goldfarb, Yael;Sorski, Liat;Melamed, Rivka;Rosenne, Ella;Ben-Eliyahu, Shamgar
通过生物反应调节剂进行免疫刺激是肿瘤免疫治疗的常见方法。 IL-12 在各种动物研究中被发现有效，但临床试验显示成功有限。然而，除其他差异外，动物模型在使用 IL-12 时不会模拟心理或生理压力，而癌症患者在接受免疫刺激剂治疗时经常会经历痛苦。因此，在当前的研究中，我们评估了持续应激对 IL-12 免疫刺激功效的影响。 F344大鼠在施用IL-12前2小时开始接受药理学应激范例（连续施用β-肾上腺素能激动剂）或20小时行为应激范例（湿笼暴露）。应激开始后 26 小时，我们研究了已知反映 IL-12 免疫刺激影响的指标，包括不同免疫区室中 NK 细胞的数量和活性，以及对 MADB106 肺肿瘤定植的体内抵抗力。结果表明，药理学和行为应激范例均显着降低了未应激 IL-12 治疗动物中明显的边缘肺 NK 细胞数量和活性的增加。此外，应激动物表现出较低的 IL-12 诱导的 MADB106 肺清除率改善，这是一个明显取决于总边缘肺 NK 活性的体内指数。压力的这些有害影响在男性中比在女性中更为突出。总体而言，研究结果表明，无论压力对基线免疫措施的影响如何，长时间的压力暴露都会破坏同时免疫刺激治疗的功效。神经内分泌和细胞介导机制尚不清楚，但这些发现的潜在临床影响值得在使用免疫刺激剂的临床试验中考虑。
Immune stimulation by biological response modifiers is a common approach in tumor immunotherapy. IL-12 was found effective in various animal studies, but clinical trials showed limited success. However, among other differences, animal models do not simulate psychological or physiological stress while employing IL-12, whereas cancer patients often experience distress while treated with immunostimulants. Thus, in the current study we assessed the impact of continuous stress on the efficacy of IL-12 immunostimulation. F344 rats were subjected to a pharmacological stress paradigm (continuous administration of a β-adrenergic agonist) or to a 20-hr behavioral stress paradigm (wet cage exposure) commencing 2 hrs before IL-12 administration. Twenty-six hr after stress initiation, we studied indices known to reflect IL-12 immunostimulatory impacts, including NK cell numbers and activity in different immune compartments, and in vivo resistance to MADB106 lung tumor colonization. The results indicated that both the pharmacological and behavioral stress paradigms significantly reduced the increase in the number and activity of marginating-pulmonary NK cells evident in non-stressed IL-12 treated animals. Additionally, stressed animals exhibited a lower IL-12-induced improvement of MADB106 lung clearance, an in vivo index that markedly depends on total marginating-pulmonary NK activity. These deleterious effects of stress were more prominent in males than in females. Overall, the findings demonstrate that prolonged stress exposure can disrupt the efficacy of simultaneous immunostimulatory treatments, irrespective of stress effects on baseline immune measures. Neuroendocrine and cellular mediating mechanisms are yet unknown, but the potential clinical ramifications of these findings warrant consideration in clinical trials employing immunostimulatory agents.
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