asialo-gm1-ganglioside and Granuloma--Respiratory-Tract

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.

Topics: Adjuvants, Immunologic; Animals; Antigens, Helminth; B-Lymphocytes; B7-1 Antigen; CD40 Antigens; CpG Islands; Cytokines; Epitopes, T-Lymphocyte; Female; G(M1) Ganglioside; Granuloma, Respiratory Tract; Immunoglobulin Isotypes; Immunosuppressive Agents; Injections, Intraperitoneal; Interferon-gamma; Interleukin-10; Interleukin-12; Killer Cells, Natural; Lung; Lymphopenia; Macrophage Activation; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotides; Ovum; RNA, Messenger; Schistosoma mansoni; Th2 Cells; Up-Regulation