Lieberman M D, Nishioka K, Redmond H P, Daly J M
Division of Surgical Oncology, University of Pennsylvania School of Medicine, Philadelphia.
Ann Surg. 1992 Feb;215(2):157-65. doi: 10.1097/00000658-199202000-00011.
Nutrient substrates have been shown to enhance cell-mediated immunity, but their role as adjuvants to immunotherapy has not been previously determined. This study evaluated L-arginine as an essential substrate for optimal generation of lymphokine-activated killer (LAK) cells. This experiment also assessed supplemental dietary L-arginine as a means to potentiate the host antitumor response to interleukin-2 (IL-2) in a murine neuroblastoma (NRB) model. A/J mice received 1% arginine or isonitrogenous 1.7% glycine in addition to a regular diet 14 days before subcutaneous inoculation with C1300 NRB cells. Twenty-four hours later, animals received low (1 x 10(6) U/kg three times a day) or high (3 x 10(6) U/kg three times a day) doses of IL-2 or saline intraperitoneally for 4 days. On days 4 and 10 post-C1300 NRB inoculation, mice were killed for assessment of natural killer cell and tumor specific cytotoxicity. Remaining animals were followed for tumor incidence, tumor growth, and duration of host survival. Interleukin-2 therapy in mice receiving dietary arginine compared with those receiving glycine resulted in significantly augmented natural killer cell cytotoxicity (day 4) and generation of specific tumoricidal mechanisms (day 10). The addition of dietary arginine to low-dose IL-2 therapy significantly diminished C1300 NRB engraftment (p less than 0.05) and growth (p less than 0.001) and prolonged the duration of host survival (p less than 0.05) compared with the glycine treatment group. In vitro studies demonstrated that L-arginine is an essential substrate for optimal generation of LAK cells. Thus, supplemental dietary L-arginine enhances lymphocyte cytotoxic mechanisms and potentiates IL-2 immunotherapy.
营养底物已被证明可增强细胞介导的免疫，但它们作为免疫治疗佐剂的作用此前尚未确定。本研究评估了L-精氨酸作为淋巴因子激活的杀伤（LAK）细胞最佳生成所必需的底物。该实验还评估了补充膳食L-精氨酸作为在小鼠神经母细胞瘤（NRB）模型中增强宿主对白细胞介素-2（IL-2）抗肿瘤反应的一种手段。在皮下接种C1300 NRB细胞前14天，A/J小鼠除常规饮食外，还接受1%精氨酸或等氮的1.7%甘氨酸。24小时后，动物腹腔内接受低剂量（1×10⁶ U/kg，每日3次）或高剂量（3×10⁶ U/kg，每日3次）的IL-2或生理盐水，持续4天。在接种C1300 NRB后的第4天和第10天，处死小鼠以评估自然杀伤细胞和肿瘤特异性细胞毒性。对其余动物观察肿瘤发生率、肿瘤生长和宿主存活时间。与接受甘氨酸的小鼠相比，接受膳食精氨酸的小鼠进行白细胞介素-2治疗后，自然杀伤细胞细胞毒性（第4天）和特异性杀瘤机制的生成（第10天）显著增强。与甘氨酸治疗组相比，在低剂量IL-2治疗中添加膳食精氨酸可显著减少C1300 NRB的植入（p<0.05）和生长（p<0.001），并延长宿主存活时间（p<0.05）。体外研究表明，L-精氨酸是LAK细胞最佳生成所必需的底物。因此，补充膳食L-精氨酸可增强淋巴细胞细胞毒性机制并增强IL-2免疫治疗效果。
