COMBINATIONS OF THE CYTOKINES IL-12, IL-2 AND IFN-α SIGNIFICANTLY AUGMENT WHEREAS THE CYTOKINE IL-4 SUPPRESSES THE CYTOKINE-INDUCED ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY OF MONOCLONAL ANTIBODIES 17-1A AND BR55-2

Abstract

Since some cytokines effectively enhance the cytotoxicity of monoclonal antibodies, we investigated whether a combination of cytokines can augment the antibody-dependent cellular cytotoxicity (ADCC) of monoclonal antibodies 17-1A and BR55-2 against the colorectal carcinoma cell line HT29. Since monocytes/macrophages are important effector cells for ADCC, we used a new flow cytometric cytotoxicity assay, which allows the analysis of long-term-ADCC exerted by these cells. In our previous studies with peripheral blood mononuclear cells from normal donors, we found that IL-2, IL-12 and IFN-α increase ADCC. Therefore, we examined whether combination of these three cytokines with IL-2, IL-4, IL-6, IL-10, IL-12, IFN-α, IFN-γ, GM-CSF, M-CSF and TNF-α may yield higher ADCC than obtained by the application of single cytokines. Indeed, we found that the combinations IL-2/IFN-α, IL-2/IL-12 and IL-12/IFN-α potentiated ADCC. Interestingly, the ineffective single cytokines TNF-α and GM-CSF in the combinations IL-2/TNF-α, IFN-α/TNF-α and IFN-α/GM-CSF also proved to enhance ADCC. In contrast, IL-4 significantly suppressed the IL-2, IL-12 and IFN-α-induced ADCC. In addition, the immunosuppressive cytokine IL-10 in higher concentrations significantly suppressed the IL-12-induced-ADCC. Our results may be useful to find combinations of cytokines and mAb for the treatment of cancer.