ATTENUATION OF INTERLEUKIN 2-INDUCED PULMONARY VASCULAR LEAK SYNDROMEBY LOW-DOSES OF ORAL METHOTREXATE

Pulmonary vascular leak induced in mice by interleukin 2 (IL-2) was at tenuated by pretreatment with single or multiple doses of oral methotr exate. Methotrexate also attenuated pulmonary vascular leak when eithe r larger doses of IL-2 or when lymphokine-activated killer (LAK) cells or LAK cells plus IL-2 were administered. Lymphoid infiltrates in the lungs of mice treated with IL-2 and methotrexate were significantly l ower. The number of mice surviving treatment with high doses of IL-2 w as also significantly increased when these mice were treated with meth otrexate. Methotrexate prevented the IL-2-induced increase in the numb er of splenocytes that were asialo GM(1)(+) but had no effect on Lyt 2 (+) or L3T4(+) cell content. A marginal but significant inhibition in the generation of effector splenocytes that were cytolytic to either Y AC or MCA-205 tumor targets was observed in mice treated with methotre xate and IL-2. In vivo studies indicated that methotrexate did not com promise the antitumor efficacy of treatment regimens that contained IL -2, LAK cells, or IL-2 and LAK cells. These results demonstrate the po tential clinical utility of methotrexate in attenuating pulmonary vasc ular Leak induced by IL-2 without compromising its efficacy. One poten tial mechanism of action of methotrexate is related to its ability to stimulate the release of adenosine followed by the inhibition of the a dhesion of leukocytes to the IL-2-activated endothelium.