INTERLEUKIN-2 INDUCES INCREASED PLATELET-ENDOTHELIUM INTERACTIONS - APOTENTIAL MECHANISM OF TOXICITY

Cancer immunotherapy with interleukin-2 (IL-2) is limited by side effe cts that may cause organ dysfunction. The role of platelets in the gen eration of IL-2-induced organ dysfunction has not been studied, althou gh various studies have shown that IL-2 therapy activates both platele ts and the vascular endothelium. We hypothesized that IL-2 therapy may enhance the thrombogenic response to inflammatory stimuli through inc reased platelet-endothelial interactions and that these effects could lead to the development of organ dysfunction. C57Bl/6 mice were treate d with IL-2 intraperitoneally for 2 hours (short term) or 2 to 5 days (long term) and prepared for in vivo microscopy of the ear microcircul ation. Mice were injected intra-arterially with fluorescein isothiocya nate conjugated to bovine serum albumin (FITC-BSA), Blue light activat ion of the FITC-BSA in ear arterioles induced thrombus formation, The time to initial thrombus formation was measured as an index of thrombo genicity. Platelet function was analyzed by aggregometry and platelet expression of IL-2 receptors, and the adhesion molecule lymphocyte fun ction-associated antigen-1 (LFA-1) was analyzed by flow cytometry, Org an dysfunction was evaluated by serum markers. The administration of b oth short-term and longterm IL-2 reduced the time to initial thrombus formation as compared with controls. In vitro platelet aggregometry re vealed no acute alterations in platelet function; however, long-term I L-2 treatment resulted in decreased disaggregation rates, There were n o platelet IL-2 receptors present, and the expression of the adhesion molecule LFA-1 was not altered by IL-2. Increased thrombogenicity occu rred before the generation of organ dysfunction. These data suggest th at increased platelet adherence induced by IL-2 is caused by effects o n the endothelium that could result in microvascular thrombus formatio n and contribute to organ dysfunction.