The long term goal of our research is to investigate the relationship of cytokine-mediated events in the microcirculation to various pathophysiological states. Cytokines mediate complex interactions between immune effector cells and the microvascular endothelium. Multiple studies using in vitro models have studied these interactions, but few have evaluated the nature and mechanism of these interactions and resulting microvascular effects in vivo. This research proposal investigates the in vivo microvascular effects of the cytokine interleukin-2 (IL-2). Although IL-2 mediates the regression of cancer, clinical application has been limited by systemic toxicities related to the development of a """"""""vascular leak syndrome"""""""". Intravital microscopy will be used to directly observe and quantitate the in vivo microvascular effects that occur with IL-2 therapy. These microvascular (physiologic) alterations will be correlated with histological (anatomic) changes in the microcirculation and the development of systemic (clinical) effects to better understand the mechanism of the """"""""vascular leak syndrome"""""""". Secondarily induced cytokines (TNF, IL-1) may be important mediators of the microvascular effects and systemic toxicities induced by IL-2. Mice will be treated with these. Acute and chronic microvascular and clinical alterations will then be compared with those caused by IL-2. By measuring plasma concentrations of secondarily induced cytokines after treatment with IL-2, and using inhibitors/antagonists of secondarily induced cytokines, we will determine whether particular cytokines are responsible for specific IL-2 induced microvascular and systemic effects. Any gain in therapeutic efficacy achieved by the inhibition of IL-2 induced toxicities requires the preservation of antitumor efficacy. We will use a murine tumored model to determine whether agents which abrogate, the microvascular and systemic effects of IL-2 also alter antitumor efficacy. These studies hold potential for extending the therapeutic efficacy and clinical application of IL-2 therapy for cancer. Recent reports suggest that IL-2 induces interactions between activated immune effector cells and the tumor microcirculation which may be an important mechanism of cytokine mediated tumor cell killing in vivo. Since individual endothelial cells supply the nutrients to thousands of tumors cells, the concept of an antiangiogenic approach to cancer treatment may hold promise. We further aim to develop a chronic murine tumor microcirculation model to pursue this antiangiogenic mechanism of cytokine mediated antitumor efficacy.
