Neuroimmunology Research Unit, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel.
Brain Behav Immun. 2011 May;25(4):727-35. doi: 10.1016/j.bbi.2011.01.014. Epub 2011 Jan 28.
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 h behavioral stress paradigm (wet cage exposure) commencing 2h before IL-12 administration. Twenty-six hours 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.
免疫刺激剂的免疫刺激作用是肿瘤免疫治疗的一种常见方法。IL-12 在各种动物研究中被证明是有效的，但临床试验显示其效果有限。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应激，而癌症患者在接受免疫刺激剂治疗时常常感到痛苦。因此，在目前的研究中，我们评估了持续应激对 IL-12 免疫刺激作用的影响。F344 大鼠接受药理学应激范式（连续给予β-肾上腺素能激动剂）或 20 小时行为应激范式（湿笼暴露），在给予 IL-12 前 2 小时开始。应激开始后 26 小时，我们研究了已知反映 IL-12 免疫刺激作用的指标，包括不同免疫区室中 NK 细胞的数量和活性，以及体内对 MADB106 肺肿瘤定植的抵抗力。结果表明，药理学和行为应激范式均显著降低了非应激性 IL-12 治疗动物中边缘肺 NK 细胞数量和活性增加的程度。此外，应激动物表现出较低的 IL-12 诱导的 MADB106 肺清除率改善，这是一个依赖于总边缘肺 NK 活性的体内指标。这些应激的有害影响在雄性中比在雌性中更为明显。总的来说，这些发现表明，长期应激暴露会破坏同时进行的免疫刺激治疗的疗效，而不论应激对基线免疫措施的影响如何。神经内分泌和细胞介导的机制尚不清楚，但这些发现的潜在临床意义值得在使用免疫刺激剂的临床试验中考虑。
