Abstract
IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8+ T and NK1.1(high) cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / administration & dosage*
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Adjuvants, Immunologic / physiology
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Animals
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Antibodies, Monoclonal / administration & dosage*
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Antibodies, Monoclonal / physiology
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Antigens, Ly
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Antigens, Surface / biosynthesis
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / agonists
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Antineoplastic Agents / blood
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Antineoplastic Agents / immunology
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Line, Tumor
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Down-Regulation / genetics
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Down-Regulation / immunology
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Forkhead Transcription Factors / antagonists & inhibitors
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Forkhead Transcription Factors / biosynthesis
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Hyaluronan Receptors / biosynthesis
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Interleukin-2 / administration & dosage*
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Interleukin-2 / blood
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Interleukin-2 / genetics
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Interleukin-2 / immunology*
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Killer Cells, Natural / cytology
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lectins, C-Type / biosynthesis
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Lung Neoplasms / immunology
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Lung Neoplasms / secondary
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Lung Neoplasms / therapy
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Lymphocyte Count
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Melanoma, Experimental / immunology
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Melanoma, Experimental / therapy
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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NK Cell Lectin-Like Receptor Subfamily B
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Neoplasm Transplantation
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / agonists
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Recombinant Proteins / blood
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Recombinant Proteins / immunology
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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Antigens, Ly
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Antigens, Surface
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Antineoplastic Agents
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Hyaluronan Receptors
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Interleukin-2
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Klrb1c protein, mouse
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Lectins, C-Type
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NK Cell Lectin-Like Receptor Subfamily B
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Recombinant Proteins