Combinations of the cytokines IL-12, IL-2 and IFN-alpha significantly augment whereas the cytokine IL-4 suppresses the cytokine-induced antibody-dependent cellular cytotoxicity of monoclonal antibodies 17-1A and BR55-2.
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-alpha increase ADCC. Therefore, we examined whether combination of these three cytokines with IL-2, IL-4, IL-6, IL-10, IL-12, IFN-alpha, IFN-gamma, GM-CSF, M-CSF and TNF-alpha may yield higher ADCC than obtained by the application of single cytokines. Indeed, we found that the combinations IL-2/IFN-alpha, IL-2/IL-12 and IL-12/IFN-alpha potentiated ADCC. Interestingly, the ineffective single cytokines TNF-alpha and GM-CSF in the combinations IL-2/TNF-alpha, IFN-alpha/TNF-alpha and IFN-alpha/GM-CSF also proved to enhance ADCC. In contrast, IL-4 significantly suppressed the IL-2, IL-12 and IFN-alpha-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.
Flieger
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Medizinische Klinik und Poliklinik I, Allgemeine Innere Medizin, Universität Bonn, Bonn, Germany. Flieger@uni-bonn.de
Spengler
U
U
Beier
I
I
Sauerbruch
T
T
Schmidt-Wolf
I
I
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology*; D003110:Colonic Neoplasms; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007370:Interferon Type I; D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12; D015847:Interleukin-4