RESTORATION OF INTERLEUKIN-2 PRODUCTION IN TUMOR-BEARING RATS THROUGHREDUCING TUMOR-DERIVED TRANSFORMING GROWTH-FACTOR-BETA BY TREATMENT WITH BLEOMYCIN

We studied mechanisms of immunosuppression caused by tumor-derived tra nsforming growth factor-beta (TGF beta) and restoration of the immune response by treatment with bleomycin in rats bearing KDH-8 hepatoma. I nterleukin-2 (IL-2) production from splenocytes of KDH-8-tumor-bearing rats progressively decreased as the KDH-8 tumor grew. IL-2 production from concanavalin-A-stimulated normal rat splenocytes was signficiant ly inhibited by in vitro cultured KDH-8-tumor-cell-conditioned medium; this inhibition could be blocked by neutralizing the conditioned medi um with anti-TGF beta antibody. TGF beta activities were found in KDH- 8-tumor-tissue-conditioned medium without acid treatment and were foun d in tumor-cell-conditioned medium after acid treatment; TGF beta mRNA and TGF beta protein were found in cultured KDH-8 tumor cells. These results suggested that the KDH-8-tumor-derived TGF beta might be invol ved in the inhibition of IL-2 production from splenocytes. To determin e whether bleomycin chemotherapy could reduce tumor-derived TGF beta a nd restore the immune responses, we treated KDH-8 tumor-bearing rats w ith bleomycin (5 mg/kg, one shot) at an appropriate time (before the o ccurrence of immunosuppression) resulting in a significiant reduction of TGF beta activity in KDH-8 tumor tissues and restoration of IL-2 pr oduction from splenocytes of tumor-bearing rats; KDH-8 tumor growth ul timately regressed. In vitro experiments also showed that TGF beta act ivity, mRNA expression, and protein synthesis in KDH-8 tumor cells wer e reduced by bleomycin treatment, and that bleomycin-treated-KDH-8-tum or-cell-conditioned medium did not inhibit IL-2 production from normal rat splenocytes. These results suggest that bleomycin treatment resto red IL-2 production in tumor-bearing rats through reducing the tumor-d erived TGF beta.