Pathophysiology of interleukin-two induced neurologic toxicity

Interleukin-2 (IL-2) induces neuropsychiatric toxicity in patients, which is often dose-limiting and currently not well understood due to lack of suitable experimental methods. We therefore evaluated a number of experimental techniques to quantify changes in the brain vasculatures in a well-characterized IL-2 treatment murine model. Direct measurement of small molecule accumulation, wet versus dry brain weight comparison, and proton density MRI lacked sensitivity and reliability to detect small changes in the brain water content. Successful methods included dynamic contrast enhanced (DCE) MRI and immunohistochemistry using specific endothelial markers to identify vasodilation in carefully matched regions of the mouse brain. Both methods demonstrated significant vasodilation of the brain blood vessels following IL-2 treatment. DCE MRI further indicated that IL-2 increased brain blood vessel permeability to the contrast agent. Using these techniques, we evaluated the mechanism involved in IL-2- induced neuropsychiatric toxicity. We initially established that mice exhibited behavioral changes following IL-2 treatment, indicating that IL-2 affected the brain in the murine model as in patients. The spontaneous movement, rearing, and grooming significantly decreased by day 2 following IL-2 treatment in the C3H/HeN mice, while the motor strength and coordination of these mice were affected by day 4. Vasodilation and microvascular permeability evaluated by immunohistochemistry and DCE MRI were not iv observed until day 4, suggesting that IL-2-induced behavioral changes occurred before detectable vasodilation and microvascular permeability. Further experiments established that IL-2 mediates its cardiovascular toxicity via its receptor on leukocytes, instead of a direct action on endothelial cells. This finding supports the concept that the dose-limiting toxicities associated with IL-2 therapy are mediated by the secondary inflammatory cytokine storm. We therefore evaluated the role of nitric oxide (NO) produced by endothelial NO synthase (eNOS) in vascular changes in the brain following IL-2 treatment. The data indicated that activation of eNOS-mediated changes in vascular permeability and vasodilation correlate with motor function changes induced by IL-2, while changes in spontaneous behavior following IL-2 treatment are not mediated by NO.