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. 1997 Nov 17;186(10):1623-31.
doi: 10.1084/jem.186.10.1623.

CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity

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CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity

R S Chu et al. J Exp Med. .

Abstract

Synthetic oligodeoxynucleotides (ODN) that contain unmethylated CpG motifs (CpG ODN) induce macrophages to secrete IL-12, which induces interferon (IFN)-gamma secretion by natural killer (NK) cells. Since these cytokines can induce T helper 1 (Th1) differentiation, we examined the effects of coadministered CpG ODN on the differentiation of Th responses to hen egg lysozyme (HEL). In both BALB/c (Th2-biased) and B10.D2 (Th1-biased) mice, immunization with HEL in incomplete Freund's adjuvant (IFA) resulted in Th2-dominated immune responses characterized by HEL-specific secretion of IL-5 but not IFN-gamma. In contrast, immunization with IFA-HEL plus CpG ODN switched the immune response to a Th1-dominated cytokine pattern, with high levels of HEL-specific IFN-gamma secretion and decreased HEL-specific IL-5 production. IFA-HEL plus CpG ODN also induced anti-HEL IgG2a (a Th1-associated isotype), which was not induced by IFA-HEL alone. Control non-CpG ODN did not induce IFN-gamma or IgG2a, excepting lesser increases in B10.D2 (Th1-biased) mice. Thus, CpG ODN provide a signal to switch on Th1-dominated responses to coadministered antigen and are potential adjuvants for human vaccines to elicit protective Th1 immunity.

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Figures

Figure 1
Figure 1
Th1-associated antigen-specific IgG2a responses are induced by immunization of BALB/c mice with IFA-HEL-CpG ODN but not IFA-HEL-non–CpG ODN. (A–C). Mice were injected i.p. with CFA-HEL (a control for a Th1-dominated response), IFA-HEL (a control for a Th2-dominated response), or IFA-HEL with 100 μg of CpG ODN 1826 or non–CpG ODN 1745. Sera were collected from mice 15–18 d after injection and assayed by ELISA for: (A) anti-HEL IgG2a, an isotype associated with Th1-dominated responses; (B) anti-HEL IgG1; and (C) anti-HEL total Ig response. A–C represent data from a single experiment representative of three similar experiments. (D) BALB/c mice were immunized as above, except that 30 μg of CpG ODN 1585, non–CpG ODN 1972, CpG ODN 1760, or non–CpG ODN 1908 was used for each mouse. Anti-HEL IgG2a antibodies were detected by serum ELISA. Data shown in D are representative of three similar experiments.
Figure 2
Figure 2
CpG ODN enhance HEL-specific IFN-γ production by BALB/c splenocytes. Mice were immunized as in Fig. 1 with 100 μg ODN/mouse in A and 30 μg ODN/mouse in panel B. After 3 wk, splenocytes were isolated and incubated with HEL (closed circles) or medium alone (open circles). ELISA spot assay was performed and spots were quantitated by a computerized image analysis program. Each point represents the mean number of spots per well for one mouse (assayed in duplicate); horizontal bars indicate the mean of points for each group of mice. Similar results were observed in five independent experiments with CpG- and non–CpG ODN in BALB/c mice.
Figure 3
Figure 3
ELISA spot assessment of IFN-γ production by splenocytes from immunized BALB/c mice. Pictures show representative images of ELISA spot wells from the experiment shown in Fig. 2 A. The number of spots, as quantitated by an image analysis program, is indicated next to each well. Each well contained HEL (100 μg/ml) and 106 splenocytes isolated from mice immunized with IFA-HEL (A), IFA-HEL-non–CpG ODN 1745 (B) or IFA-HEL-CpG ODN 1826 (C).
Figure 4
Figure 4
CpG ODN decrease HEL-specific IL-5 production by BALB/c splenocytes. Mice were immunized as in Fig. 2 (30 μg ODN/mouse), and splenocytes were harvested for in vitro restimulation with or without HEL. ELISA spot analysis was performed for IL-5. The data are representative of five similar experiments with CpG- and non–CpG ODN in BALB/c mice.
Figure 5
Figure 5
Induction of HEL-specific IFN-γ responses by CpG ODN in B10.D2 mice. B10.D2 mice were immunized as in Fig. 1, except that ODN were used at 30 μg per mouse. Three weeks after immunization, HEL-specific production of IFN-γ by splenocytes was measured by ELISA spot assay as in Fig. 2. The data shown are representative of three similar experiments.

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