Cancer immunotherapy with
interleukin-2 (IL-2) is limited by side effects that may cause organ dysfunction. The role of platelets in the generation of IL-2-induced organ dysfunction has not been studied, although various studies have shown that
IL-2 therapy activates both platelets and the vascular endothelium. We hypothesized that
IL-2 therapy may enhance the thrombogenic response to inflammatory stimuli through increased platelet-endothelial interactions and that these effects could lead to the development of organ dysfunction. C57BI/6 mice were treated 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 microcirculation. Mice were injected intra-arterially with
fluorescein isothiocyanate conjugated to
bovine serum albumin (
FITC-BSA). Blue light activation of the
FITC-BSA in ear arterioles induced
thrombus formation. The time to initial
thrombus formation was measured as an index of thrombogenicity. Platelet function was analyzed by aggregometry and platelet expression of
IL-2 receptors, and the adhesion molecule
lymphocyte function-associated antigen-1 (LFA-1) was analyzed by flow cytometry. Organ dysfunction was evaluated by
serum markers. The administration of both short-term and long-term
IL-2 reduced the time to initial
thrombus formation as compared with controls. In vitro platelet aggregometry revealed no acute alterations in platelet function; however, long-term
IL-2 treatment resulted in decreased disaggregation rates. There were no platelet
IL-2 receptors present, and the expression of the adhesion molecule
LFA-1 was not altered by
IL-2. Increased thrombogenicity occurred before the generation of organ dysfunction. These data suggest that increased platelet adherence induced by
IL-2 is caused by effects on the endothelium that could result in microvascular
thrombus formation and contribute to organ dysfunction.