Combined effects of interferon α and interleukin 2 on the induction of a vascular leak syndrome in mice

Abstract

Immunotherapy with interleukin 2 (IL-2) alone or in combination with lymphokine-activated killer cells can mediate tumor regression in mice and in man. Further dose escalation of IL-2 along with lymphokine-activated killer cells has been prevented by the development of a vascular leak syndrome produced by IL-2. Because we have found that interferon α (IFN-α) or tumor necrosis factor (TNF-α) has synergistic antitumor effects when administered together with IL-2, we have tested the vascular leakage induced by these lymphokine combinations. We used a murine model to quantify vascular leakage by measuring the extravasation of ¹²⁵I-albumin from the intravascular space as well as the wet and dry lung weights after treatment with different cytokines. Cytokines (or Hanks balanced salt solution) were administered to C57BL/6 mice and 4 h after the last injection the vascular leak was quantified. IFN-α alone did not cause extravasation of radiolabel or increase in wet lung weights, though when given in combination with IL-2, significantly greater extravasation (P<0.01) as well as increase in lung water weights (P<0.05) was observed compared to the response in mice treated with IL-2 alone. IFN-α in combination with IL-2 induced significant vascular leakage earlier than the response induced by IL-2 alone. For example treatment with IFN-α and IL-2 induced accumulation of 14674±605 cpm in the lungs at day 1 while IL-2 alone induced 12340±251 cpm. The degree of vascular leakage was highly related to the dose of IFN-α administered along with IL-2 and increased vascular leak syndrome was evident even at low doses (5000 units) of IFN-α. Immunosuppression of mice by pretreatment irradiation (500 rad) markedly decreased the development of vascular leak syndrome induced by IL-2 and IFN-α. Interestingly IFN-γ and TNF-α did not induce vascular leakage in the lungs when given alone, and did not add or synergize with IL-2 in causing the syndrome. Thus the administration of IFN-α in combination with IL-2 produces a dose-limiting vascular leakage that is more severe than that caused by IL-2 alone, and may be mediated, directly or indirectly by host radiosensitive cells.