Abstract
Using a Schistosoma mansoni egg-induced granuloma model, we examined the ability of CpG oligodeoxynucleotides (ODN) to suppress Th2-type cytokine expression and to prophylactically immunize against Th2-dependent pulmonary pathology. The mechanism was examined by studying Th2 response regulation in cytokine-deficient mice. Surprisingly, our findings revealed several functions of CpG DNA that were completely IL-12 independent. Most striking was the marked suppression in Th2 cytokine expression and granulomatous inflammation observed in egg/CpG-sensitized IL-12-deficient mice. Immune deviation was not dependent on NK or B cells. However, a role for IL-10, B7.1, and CD40 expression in Th2 response inhibition was suggested. Indeed, CpG ODN up-regulated all three elements in both wild-type and IL-12-deficient mice. The role of IL-10 was demonstrated in mice exhibiting combined deficiencies in IL-12 and IL-10. Here, a marked increase in egg-specific IL-4/IL-5-producing cells confirmed a role for both cytokines in Th2 response inhibition. Nevertheless, the frequency of Th2-producing cells was again reduced by CpG ODN. However, in marked contrast to IL-12-deficient animals, a significant increase in IFN-gamma-producing cells likely explains the reduced Th2 response in IL-10/IL-12-deficient mice. Thus, a novel IL-12-independent type 1-inducing pathway was revealed in the combined absence of IL-12 and IL-10. Together, these data demonstrate 1) that the Th1-promoting activity of CpG DNA is controlled by IL-12 and IL-10, and 2) that Th2 response inhibition by CpG ODN involves IL-12-independent changes in IL-10 and costimulatory molecule expression. These findings illustrate the utility of CpG DNA as adjuvants for vaccines designed to prevent Th2-dependent immunopathology.
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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Animals
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Antigens, Helminth / administration & dosage
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Antigens, Helminth / immunology
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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B7-1 Antigen / biosynthesis
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CD40 Antigens / biosynthesis
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CpG Islands / immunology*
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Cytokines / biosynthesis
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Epitopes, T-Lymphocyte / immunology
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Female
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G(M1) Ganglioside / biosynthesis
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Granuloma, Respiratory Tract / genetics
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Granuloma, Respiratory Tract / immunology*
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Granuloma, Respiratory Tract / parasitology
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Granuloma, Respiratory Tract / pathology*
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Immunoglobulin Isotypes / biosynthesis
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Immunoglobulin Isotypes / metabolism
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Immunosuppressive Agents / administration & dosage
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Injections, Intraperitoneal
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Interferon-gamma / biosynthesis
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Interferon-gamma / genetics
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Interferon-gamma / physiology
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Interleukin-10 / biosynthesis
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Interleukin-10 / deficiency
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Interleukin-10 / genetics
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Interleukin-12 / biosynthesis
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Interleukin-12 / deficiency
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Interleukin-12 / genetics
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Interleukin-12 / physiology*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lung / immunology
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Lung / metabolism
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Lymphopenia / genetics
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Lymphopenia / immunology
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Macrophage Activation / genetics
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oligonucleotides / administration & dosage
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Oligonucleotides / immunology*
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Ovum / immunology*
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RNA, Messenger / biosynthesis
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Schistosoma mansoni / immunology*
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Th2 Cells / parasitology
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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Antigens, Helminth
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B7-1 Antigen
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CD40 Antigens
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Cytokines
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Epitopes, T-Lymphocyte
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Immunoglobulin Isotypes
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Immunosuppressive Agents
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Oligonucleotides
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RNA, Messenger
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Interleukin-10
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Interleukin-12
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G(M1) Ganglioside
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asialo GM1 ganglioside
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Interferon-gamma