CARDIOTOXICITY OF HUMAN RECOMBINANT INTERLEUKIN-2 IN RATS - A MORPHOLOGICAL-STUDY

Background. One of the side effects of interleukin 2 (IL-2) cancer immunotherapy in humans is the vascular leak syndrome, which is frequently associated with depression of myocardial function, myocarditis, and myocardial necrosis. Methods and Results. To investigate this cardiotoxicity, IL-2 (three doses of 5 x 10(5) Cetus units/day i.p.) was given to rats for 2, 3, or 5 days. Heart, lung, liver, spleen, and kidney tissues were studied by light and electron microscopy and with immunoperoxidase techniques. Cardiac changes consisted of focal lymphocytic and eosinophilic infiltration, myocyte vacuolization, myofibrillar loss, and necrosis. Ultrastructural alterations included swelling of endothelial cells, with dissociation of intercellular junctions, migration of lymphocytes into the interstitium, and interstitial hemorrhage and edema. Close contact between infiltrating lymphocytes, particularly large granular lymphocytes, and cardiac myocytes was often observed in areas of tissue damage. All lesions were more severe on day 5 than on days 2 and 3. Immunoperoxidase stains demonstrated asialo GM1 ganglioside antibody-positive, granular lymphocytes to be much more frequent in myocardium of IL-2-treated rats than in that of control rats. Conclusions. Although we cannot exclude the possibility of a direct toxic effect of IL-2 on myocytes, our observation's suggest that the myocardial damage produced by this agent is triggered by IL-2-activated lymphocytes that exert cytolytic effects, first on endothelial cells and then on cardiac myocytes, thus producing lesions that involve both the cardiac microcirculation and the muscle cells.