CEREBROVASCULAR CONSEQUENCES OF SYSTEMIC RIL-2 INFUSION

初步临床试验表明， 给予淋巴因子激活的杀伤（LAK）细胞+ rIL-2 以诱导某些类型的转移性肿瘤的实质性消退， 肿瘤 虽然有时有效，这种免疫疗法显示， 在杀死肿瘤细胞所需的剂量水平下的毒性。 有毒 效应似乎是继发于IL-2相关的全身性 微血管通透性增加，到目前为止，IL-2诱导 在脾，肝， 肺和肾血管床。 目前的目标是 建议是探索脑微血管的潜力， rIL-2 i.v. 管理。 这将通过评估IL-2来实现 诱导1）脑血管通透性的改变， 外源性和内源性来源的大分子，2）变化 软膜血管对生理刺激的反应性，如评估的 通过颅窗研究，3）改变超微结构特征 脑血管系统和周围脑实质， （4）IL-2相关的局部脑血流量变化。 这些参数将在麻醉大鼠中进行急性检查， 以及在慢性啮齿动物模型中， 长期IL-2给药的后遗症可以更充分地 评估。 希望这些研究将有助于澄清 临床报告的神经系统症状的潜在机制 IL-2诱导以及预测延迟或 持续的CNS不良反应，尽管明显的 停药后的症状。

Preliminary clincical trails have shown the systemic administration of lymphokine-activated killer (LAK) cells + rIL-2 to induce substantial regression of some types of metastatic tumor. Although somtimes efficacious, this immunotherapy shows toxicity at dosage levels required for tumor cell killing. Toxic effects appear to be secondary to an IL-2 associated generalized increase in microvascular permeability, and, to date, IL-2 induced abnormalities have been observed in the splenic, hepatic, pulmonary and renal vascular beds. The objective of the present proposal is to explore the potential for cerebral microvascular alteration and brain parenchymal chnage subsequent to rIL-2 i.v. adminstration. This will be accomplished by evaluating IL-2 induced 1) alterations in cerebrovascular permeability to macromolecules of exogenous and endogenous origins, 2) changes in pial vascular reactivity to physiologic stimuli, as assessed through cranial window studies, 3) altered ultrastructural features of the cerebral vasculature and surrounding brain parenchyma, and 4) IL-2 associated changes in regional cerebral blood flow. These parameters will be examined acutely in anesthesized rats as well as in a chronic rodent model in which the cerebrovascular sequelae of longer term IL-2 administration can be more fully evaluated. It is hoped that these studies will help to clarify the mechanisms underlying clinically-reported neurological symptoms induced by IL-2 as well as to predict the likelihood of delayed or enduring adverse CNS effects despite the disappearance of overt symptoms upon treatment withdrawal.