Interleukin-2 Does Not Sequester Activated Lymphocytes into Lung Lymph of Sheep

Purpose of study: Interleukin-2 (IL-2) is a potent activator of lymphocytes, but its effectiveness as an anticancer agent is compromised by several adverse side effects including pulmonary edema. One explanation for the pulmonary toxicity of IL-2 is that activated lymphocytes directly induce the pulmonary vascular endothelium to become more leaky. Methods: To test this hypothesis the number of total lymphocytes, γδ T cells, and CD2-positive cells (αβ T cells and natural killer cells) in peripheral blood and lung lymph of sheep were compared before and after IL-2 infusion. Hemodynamic and lymph dynamic changes were also evaluated. Results: IL-2 decreased mean aortic pressure, increased cardiac output, lowered systemic vascular resistance, and doubled lung lymph flow (P≤ 0.05), but had no effect on plasma or lymph oncotic pressure. The lymph protein concentration and the lymph-to-plasma protein concentration ratio were not different after IL-2 infusion. IL-2 had no effect on the number of total lymphocytes, γδ T cells, or CD2-positive cells in the peripheral blood. In contrast, the number of total lymphocytes, γδ T cells, and CD2-positive cells in lung lymph decreased significantly (P≤ 0.05). Conclusions: The lymphocyte populations decreased more than could be explained by the increase in lymph flow, demonstrating that lung lymphocytes were not reduced simply by dilution. These results imply that the pulmonary edema associated with IL-2 is not caused by activated lymphocytes.