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International Immunology Advance Access published online on April 30, 2008
International Immunology, doi:10.1093/intimm/dxn036
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation

Guihua Jin1, Toshio Hirano1,2 and Masaaki Murakami1

1 Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Osaka, Japan
2 Laboratory of Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

Correspondence to: Correspondence to: M. Murakami; E-mail: murakami{at}molonc.med.osaka-u.ac.jps

Combination treatment consisting of IL-2 together with anti-IL-2 mAbs results in markedly larger increases in the numbers of CD8+ T cells, dendritic cells (DCs) and NK cells in vivo compared with the results observed with injections of IL-2 or the antibodies alone. We previously showed that this combination treatment overcomes the problems associated with the short half-life of IL-2 in vivo. Importantly, the combination treatment but not IL-2 or the anti-IL-2 mAbs alone protected the mice against tumor metastases in the lungs. Here we have investigated which cell types are responsible for this protective immunity against tumors. We analyzed tumor metastases in mice that were depleted of DCs, CD8+ T cells or NK cells. DC-deficient, diphtheria toxin receptor-expressing mice injected with diphtheria toxin as well as B cell- and T cell-deficient RAG-2-knockout mice were protected against tumors after they were administered the combination treatment. On the other hand, mice that were depleted of NK cells using anti-asialo-GM1 antibodies did not exhibit the anti-tumor activity after treatment with IL-2 combined with anti-IL-2 mAbs. Thus, these data demonstrate that NK cells, but not DCs, or CD8+ T cells mediate the anti-tumor effect induced by this combination treatment. Therefore, combining neutralizing anti-IL-2 mAbs with IL-2 may be clinically useful to effectively enhance IL-2-mediated NK cell activities.

Keywords: anti-IL-2 antibody, IL-2, NK cells, T cells

Transmitting editor: T. Saito

Received 17 December 2007, accepted 23 March 2008.


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