Combined effects of interferon alpha and interleukin 2 on the induction of a vascular leak syndrome in mice.
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 alpha (IFN-alpha) or tumor necrosis factor (TNF-alpha) 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-alpha 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 less than 0.01) as well as increase in lung water weights (P less than 0.05) was observed compared to the response in mice treated with IL-2 alone. IFN-alpha in combination with IL-2 induced significant vascular leakage earlier than the response induced by IL-2 alone. For example treatment with IFN-alpha and IL-2 induced accumulation of 14,674 +/- 605 cpm in the lungs at day 1 while IL-2 alone induced 12,340 +/- 251 cpm. The degree of vascular leakage was highly related to the dose of IFN-alpha administered along with IL-2 and increased vascular leak syndrome was evident even at low doses (5000 units) of IFN-alpha. Immunosuppression of mice by pretreatment irradiation (500 rad) markedly decreased the development of vascular leak syndrome induced by IL-2 and IFN-alpha. Interestingly IFN-gamma and TNF-alpha 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-alpha 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.
Puri
R K
RK
Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
Rosenberg
S A
SA
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000528:radiation effects; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000633:toxicity*; D007371:Interferon-gamma / Q000008:administration & dosage; D007376:Interleukin-2 / Q000633:toxicity*; D007700:Kinetics; D008171:Lung Diseases / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins; D012711:Serum Albumin, Radio-Iodinated; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D007370:Interferon Type I; D007376:Interleukin-2; D011994:Recombinant Proteins; D012711:Serum Albumin, Radio-Iodinated; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma