CROSS-REGULATION BY IL-10 AND 1L-2 IL-12 OF THE HELPER T-CELLS AND THE CYTOLYTIC ACTIVITY OF LYMPHOCYTES FROM MALIGNANT EFFUSIONS OF LUNG-CANCER PATIENTS/

Study objective: Our previous report demonstrated that there was impai rment of local cellular immunity with elevated interleukin-10 (IL-10) and undetectable IL-12 in neoplastic pleural effusion. These findings suggest that the local immune reactions favor the T-helper type 2 (Th2 ) pathway instead of Th1 pathway. The present study was designed to ex amine whether local cellular immunity could be manipulated by IL-2 and /or IL-12 treatment, and to determine their effect on the helper T-cel l pathways and the cytolytic activity of the effusion-associated lymph ocytes (EALs). Design: Using malignant pleural effusions obtained from four patients suffering from adenocarcinoma of lung, we separated the tumor cells from the EALs with Ficol-Hypaque centrifugation, followed by Percoll density centrifugation. To test whether the cytolytic func tion of lymphocytes could be enhanced by culturing with IL-2 and/or IL -12, lymphocytes were incubated with recombinant IL-2 with/without IL- 12 for 6 days. Following this, the tumoricidal activity was assessed i n an overnight (51)chromium-release assay. Autologous tumor cells for measuring specific antitumor activity, Daudi cells susceptible to lymp hokine-activated killer cells, and NK-susceptible K562 cells were used as target cells.Measurements and results: After treatment in vitro wi th IL-2, IL-12, or IL-2 plus IL-12, the Th pathway shifted from Th2 to Th1 type (increased gamma-interferon production). To further study th e effect of cytokine treatment on the cytolytic activity of EALs, it w as found that after 6-day culturing, the EALs failed to kill any of th e three tumor targets, whereas the 6-day cultured peripheral blood lym phocytes (PBLs) gave low level of cytotoxicity against all three tumor targets. Stimulation with IL-2 alone partially restored the immunocom petence of EALs to kill the tumor targets. Stimulation with IL-12 alon e showed no significant effect on their cytolytic activity. However, I L-12 synergized with IL-2 to increase the cytolytic activity of EALs a nd PBLs against autologous tumor targets. This synergistic effect was not found for Daudi cells and K562 cells. Conclusions: These result su ggest that EALs activated with IL-12 in the presence of a low concentr ation of IL-2, which converted the EALs from Th2 pathway to Th1 pathwa y, could be an alternative source of antitumor effectors for adoptive immunotherapy of cancer.