CEREBROVASCULAR CONSEQUENCES OF SYSTEMIC RIL-2 INFUSION

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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.