IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guérin immunotherapy.
IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guérin immunotherapy.
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DOI：
10.4049/jimmunol.162.4.2399
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发表时间：
1999-02
影响因子：
4.4
通讯作者：
Yi Luo;Xiaohong Chen;Tracy M. Downs;W. DeWolf;M. O'Donnell
中科院分区：
文献类型：
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作者：
Yi Luo;Xiaohong Chen;Tracy M. Downs;W. DeWolf;M. O'Donnell
膀胱内卡介苗（BCG）加IFN-α联合治疗浅表性膀胱癌已被证明比动物研究中的任何一种单药更有效，临床研究表明疗效更高。然而，人们对IFN-alpha增强卡介苗介导的抗肿瘤活性的机制知之甚少。使用来自膀胱癌患者的PBMC，发现IFN-α显著增强BCG诱导IFN-γ产生的功效。在34名接受测试的患者中，80%的患者显示>4倍的增加。IFN-α的这种作用在对BCG的初始和记忆反应中都观察到。此外，IFN-α上调BCG诱导的IL-12和TNF-α，下调BCG诱导的IL-10。中和内源性IL-10或添加外源性IL-12为IFN-γ产生提供了进一步的协同作用。在临床实践中，观察到膀胱内IFN-α 2B（5000万单位（MU）/剂量）加速尿IFN-γ的产生，使联合治疗患者的低剂量BCG（全剂量的十分之一或三分之一）与单独使用BCG相比。这些结果表明，IFN-α是一种有效的BCG增强剂，通过促进Th 1细胞因子表达和减少Th 2细胞因子表达，使BCG诱导的免疫应答向细胞免疫途径极化。本研究为今后合理使用IFN-α联合BCG膀胱灌注治疗膀胱癌提供了免疫学依据。
Combination therapy with intravesical bacillus Calmette-Guérin (BCG) plus IFN-alpha for superficial bladder cancer has been demonstrated to be more effective than either single agent alone in animal studies and of suggested greater efficacy in clinical studies. However, the mechanism by which IFN-alpha enhances BCG-mediated antitumor activity is poorly understood. Using PBMCs from bladder cancer patients, IFN-alpha was found to substantially enhance the efficacy of BCG to induce IFN-gamma production. Among 34 patients tested, 80% showed >4-fold increase. This effect of IFN-alpha was observed in both initial and memory responses to BCG. In addition, IFN-alpha up-regulated BCG-induced IL-12 and TNF-alpha and down-regulated BCG-induced IL-10. Neutralizing endogenous IL-10 or adding exogenous IL-12 provided further synergy for IFN-gamma production. In clinical practice, intravesical IFN-alpha 2B (50 million units (MU)/dose) was observed to accelerate urinary IFN-gamma production to low-dose BCG (one-tenth or one-third of a full dose) in patients treated with combination therapy compared with BCG alone. These results suggest that IFN-alpha is a potent BCG enhancer that polarizes the BCG-induced immune response toward the cellular immune pathway by promoting Th1 cytokine expression and reducing Th2 cytokine expression. This study provides an immunological basis for future rational use of IFN-alpha in conjunction with intravesical BCG for bladder cancer immunotherapy.