Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes.
Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes.
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DOI：
10.4049/jimmunol.151.3.1235
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发表时间：
1993-08
影响因子：
4.4
通讯作者：
F. Finkelman;K. Madden;S. Morris;J. Holmes;N. Boiani;I. Katona;C. Maliszewski
中科院分区：
文献类型：
--
作者：
F. Finkelman;K. Madden;S. Morris;J. Holmes;N. Boiani;I. Katona;C. Maliszewski
阻断细胞因子和细胞因子受体之间相互作用的抗细胞因子抗体已被用于抑制内源性细胞因子功能。然而，按细胞因子/抗细胞因子单抗摩尔比约2：1的比例注射IL-4和两种中和性抗IL-4单抗中的任何一种，可增强并延长体内IL-4的活性，通过诱导脾细胞Ia的表达来衡量。虽然小鼠脾细胞Ia表达在注射游离IL-4两天后恢复到基线水平，但可溶性IL-4-抗IL-4单抗复合物在注射后3天仍可诱导Ia表达增加数倍。含有低至400 ng的IL-4的复合体在体内具有相当大的刺激活性，而注射2微克的复合体IL-4对脾细胞Ia表达的影响最大。增加抗IL-4单抗与IL-4的比例、注射抗IL-4R单抗及体内聚集可阻断含IL-4的复合体对脾细胞Ia表达的刺激作用。IL-4与非中和性抗IL-4单抗的络合物在体内不具有增强IL-4激动剂的活性。这些观察结果与中和抗IL-4单抗作为载体蛋白的可能性最一致，该载体蛋白通过阻止IL-4的排泄，并可能通过阻止其活性部位的修饰来延长IL-4在体内的半衰期。IL-4-抗-IL-4单抗的增强激活作用并不是唯一的；与游离IL-3相比，IL-3与中和性抗IL-3单抗形成的复合体刺激粘膜肥大细胞增殖的能力显著增强；与游离IL-7或IL-7与非中和性抗IL-7单抗形成的复合体相比，IL-7与中和性抗IL-7单抗形成的复合体刺激前B细胞数量的能力显著增强。这些观察表明，细胞因子和中和性抗细胞因子单抗的复合体可能提供了一种普遍有用的方法来增加体内细胞因子作用的幅度和持续时间。
Anti-cytokine antibodies that block interactions between cytokines and cytokine receptors have been used to inhibit endogenous cytokine function. However, injection of mice with mixtures of IL-4 and either of two neutralizing anti-IL-4 mAb, at a cytokine/anti-cytokine mAb molar ratio of approximately 2:1, enhances and prolongs in vivo IL-4 activity, as measured by induction of increased spleen cell Ia expression. Although splenocyte Ia expression returns to baseline two days after mice are injected with free IL-4, soluble IL-4-anti-IL-4 mAb complexes still induce several-fold increases in Ia expression 3 days after injection. Complexes that contain as little as 400 ng of IL-4 have considerable in vivo stimulatory activity, and a maximal effect on splenocyte Ia expression is induced by injection of 2 micrograms of complexed IL-4. The stimulatory effect of IL-4-containing complexes on splenocyte Ia expression can be blocked by increasing the ratio of anti-IL-4 mAb to IL-4, by injection of anti-IL-4R mAb, and by in vivo aggregation of the complexes. Complexes of IL-4 with a non-neutralizing anti-IL-4 mAb do not have increased IL-4 agonist activity in vivo. These observations are most consistent with the possibility that neutralizing anti-IL-4 mAb act as carrier proteins that increase the in vivo half-life of IL-4 by preventing its excretion, and possibly, by preventing modification of its active site. The enhanced agonist effect of IL-4-anti-IL-4 mAb complexes is not unique; complexes of IL-3 with a neutralizing anti-IL-3 mAb have a greatly increased ability, compared with free IL-3, to stimulate mucosal mastocytosis, and complexes of IL-7 with a neutralizing anti-IL-7 mAb have a greatly increased ability, compared with free IL-7 or IL-7 complexed with a non-neutralizing anti-IL-7 mAb, to stimulate an increase in pre-B cell number. These observations suggest that complexes of cytokines and neutralizing anti-cytokine mAb may provide a generally useful way to increase the magnitude and duration of cytokine effects in vivo.