CpG oligonucleotides can prophylactically immunize against Th2-mediated schistosome egg-induced pathology by an IL-12-independent mechanism.
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.
Chiaramonte
M G
MG
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Hesse
M
M
Cheever
A W
AW
Wynn
T A
TA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000947:Antigens, Helminth / Q000008:administration & dosage / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018122:B7-1 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D018899:CpG Islands / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005677:G(M1) Ganglioside / Q000096:biosynthesis; D015769:Granuloma, Respiratory Tract / Q000235:genetics / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009841:Oligonucleotides / Q000008:administration & dosage / Q000276:immunology*; D010063:Ovum / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012550:Schistosoma mansoni / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D000947:Antigens, Helminth; D018122:B7-1 Antigen; D019013:CD40 Antigens; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007132:Immunoglobulin Isotypes; D007166:Immunosuppressive Agents; D009841:Oligonucleotides; D012333:RNA, Messenger; D016753:Interleukin-10; D018664:Interleukin-12; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D007371:Interferon-gamma