THE TUMOR-BEARING STATE INDUCES AUGMENTED RESPONSES OF ORGAN-ASSOCIATED LYMPHOCYTES TO HIGH-DOSE INTERLEUKIN-2 THERAPY IN MICE

A high-dose bolus regimen for interleukin(IL)-2 administration to canc er patients frequently causes serious side-effects in which various or gans are involved. In order to reveal the mechanism of toxicities asso ciated with this regimen, we compared the augmenting effect of high-do se IL-2 on murine organ-associated lymphocytes between neoplastic and non-neoplastic states. Intraperitoneal administration of IL-2 at a dos e of 10(5) JRU (Japanese Reference Units) twice daily for 3 days led t o the death of all the syngeneic MH134-hepapotoma- or X5563-myeloma-be aring mice, whereas it had no lethal effect on non-tumor-bearing mice. Histological and morphometric analyses demonstrated that tumor-bearin g mice displayed more extensive infiltration of large granular lymphoc ytes and agranular lymphocytes in the liver and lungs than did the non -tumor-bearing mice. Large granular lymphocytes had the ultrastructura l characteristics of lymphokine-activated killer cells. Lymphocytes of ten underwent extravasation into the interstitial space and exhibited local proliferation without causing any direct injury to apposed paren chymal cells. Flow-cytometric analysis of hepatic mononuclear cells de monstrated that IL-2-receptor-beta(IL-2R beta)-bearing lymphocytes, i. e., natural killer cells and intermediate CD3 cells, were increased in number in the neoplastic state before the IL-2 injection. The present study indicates that the tumor-bearing state increases the number of organ-associated IL-2R beta(+) lymphocytes, which are then greatly amp lified by the challenge of high-dose IL-2, leading to the functional d isturbance of organs. We have further demonstrated here that an interm ittent low-dose IL-2 regimen has a potential therapeutic effect on tum or regression without causing lethal side-effects.