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IL-33 released by alum is responsible for early cytokine production and has adjuvant properties.

Rose WA, Okragly AJ, Patel CN, Benschop RJ - Sci Rep (2015)

Bottom Line: Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity.Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum.Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.

ABSTRACT
Human vaccines have used aluminium-based adjuvants (alum) for >80 years despite incomplete understanding of how alum enhances the immune response. Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity. IL-33 is proposed to be one such danger signal that is released from necrotic cells. Therefore, we investigated whether there is a role for IL-33 in the adjuvant activity of alum. We show that alum-induced cellular necrosis results in elevated levels of IL-33 following injection in vivo. Alum and IL-33 induce similar increases in IL-5, KC, MCP-1, MIP-1α and MIP-1β; many of which are dependent on IL-33 as shown in IL-33 knockout mice or by using an IL-33-neutralizing recombinant ST2 receptor. Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum. However, IL-33 is not absolutely required for alum-induced antibody responses since alum mediates similar humoral responses in IL-33 knockout and wild-type mice. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.

No MeSH data available.


Related in: MedlinePlus

Alum induces antibody responses independently of IL-33.(a) WT and IL-33 KO mice (n = 5 mice/group) were injected i.p. with PBS or alum mixed with PBS at 1:2 ratio in combination with NP-CGG then boosted i.p. on day 14 with PBS/NP-CGG. (b) C57BL/6 mice (n = 5 mice/group) were pre-treated with mouse IgG1 isotype control antibody (Ctrl) or ST2-Fc injected i.p. one hour prior to i.p. injection of PBS or alum/NP-CGG then boosted on day 14 with PBS/NP-CGG injected i.p. Antigen specific IgM, IgG and IgE serum titers were quantified via ELISA. Data are representative of at least two independent experiments. *p < 0.05 and **p < 0.01 and ***p < 0.001 KO PBS compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test). #p < 0.05 WT alum compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test).
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f7: Alum induces antibody responses independently of IL-33.(a) WT and IL-33 KO mice (n = 5 mice/group) were injected i.p. with PBS or alum mixed with PBS at 1:2 ratio in combination with NP-CGG then boosted i.p. on day 14 with PBS/NP-CGG. (b) C57BL/6 mice (n = 5 mice/group) were pre-treated with mouse IgG1 isotype control antibody (Ctrl) or ST2-Fc injected i.p. one hour prior to i.p. injection of PBS or alum/NP-CGG then boosted on day 14 with PBS/NP-CGG injected i.p. Antigen specific IgM, IgG and IgE serum titers were quantified via ELISA. Data are representative of at least two independent experiments. *p < 0.05 and **p < 0.01 and ***p < 0.001 KO PBS compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test). #p < 0.05 WT alum compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test).

Mentions: To investigate if the presence of IL-33 is necessary for the alum-induced antibody responses, WT and IL-33 KO mice were immunized with alum/NP-CGG. Both WT and IL-33 KO mice showed significantly increased antibody titers compared the PBS/NP-CGG control mice (Fig. 7a). Moreover, alum induced very similar antibody response kinetics for IgM, IgG1 and IgE in WT and IL-33 KO mice, and only IgG1 titers on day 17 in the IL-33 KO mice were significantly lower than WT mice. When WT mice were pre-treated with ST2-Fc prior to immunization with alum/NP-CGG, we did not observe any significant changes in IgM, IgG1 and IgE antibody responses (Fig. 7b), consistent with data observed in the IL-33 KO mice (Fig. 7a). While IL-33 was able to induce cytokine release and a robust secondary antibody response, these results show that alum-induced antibody responses can occur independently of IL-33.


IL-33 released by alum is responsible for early cytokine production and has adjuvant properties.

Rose WA, Okragly AJ, Patel CN, Benschop RJ - Sci Rep (2015)

Alum induces antibody responses independently of IL-33.(a) WT and IL-33 KO mice (n = 5 mice/group) were injected i.p. with PBS or alum mixed with PBS at 1:2 ratio in combination with NP-CGG then boosted i.p. on day 14 with PBS/NP-CGG. (b) C57BL/6 mice (n = 5 mice/group) were pre-treated with mouse IgG1 isotype control antibody (Ctrl) or ST2-Fc injected i.p. one hour prior to i.p. injection of PBS or alum/NP-CGG then boosted on day 14 with PBS/NP-CGG injected i.p. Antigen specific IgM, IgG and IgE serum titers were quantified via ELISA. Data are representative of at least two independent experiments. *p < 0.05 and **p < 0.01 and ***p < 0.001 KO PBS compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test). #p < 0.05 WT alum compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test).
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Related In: Results  -  Collection

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f7: Alum induces antibody responses independently of IL-33.(a) WT and IL-33 KO mice (n = 5 mice/group) were injected i.p. with PBS or alum mixed with PBS at 1:2 ratio in combination with NP-CGG then boosted i.p. on day 14 with PBS/NP-CGG. (b) C57BL/6 mice (n = 5 mice/group) were pre-treated with mouse IgG1 isotype control antibody (Ctrl) or ST2-Fc injected i.p. one hour prior to i.p. injection of PBS or alum/NP-CGG then boosted on day 14 with PBS/NP-CGG injected i.p. Antigen specific IgM, IgG and IgE serum titers were quantified via ELISA. Data are representative of at least two independent experiments. *p < 0.05 and **p < 0.01 and ***p < 0.001 KO PBS compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test). #p < 0.05 WT alum compared to KO alum groups (Two-way ANOVA with Bonferroni multiple comparison test).
Mentions: To investigate if the presence of IL-33 is necessary for the alum-induced antibody responses, WT and IL-33 KO mice were immunized with alum/NP-CGG. Both WT and IL-33 KO mice showed significantly increased antibody titers compared the PBS/NP-CGG control mice (Fig. 7a). Moreover, alum induced very similar antibody response kinetics for IgM, IgG1 and IgE in WT and IL-33 KO mice, and only IgG1 titers on day 17 in the IL-33 KO mice were significantly lower than WT mice. When WT mice were pre-treated with ST2-Fc prior to immunization with alum/NP-CGG, we did not observe any significant changes in IgM, IgG1 and IgE antibody responses (Fig. 7b), consistent with data observed in the IL-33 KO mice (Fig. 7a). While IL-33 was able to induce cytokine release and a robust secondary antibody response, these results show that alum-induced antibody responses can occur independently of IL-33.

Bottom Line: Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity.Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum.Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285.

ABSTRACT
Human vaccines have used aluminium-based adjuvants (alum) for >80 years despite incomplete understanding of how alum enhances the immune response. Alum can induce the release of endogenous danger signals via cellular necrosis which elicits inflammation-associated cytokines resulting in humoral immunity. IL-33 is proposed to be one such danger signal that is released from necrotic cells. Therefore, we investigated whether there is a role for IL-33 in the adjuvant activity of alum. We show that alum-induced cellular necrosis results in elevated levels of IL-33 following injection in vivo. Alum and IL-33 induce similar increases in IL-5, KC, MCP-1, MIP-1α and MIP-1β; many of which are dependent on IL-33 as shown in IL-33 knockout mice or by using an IL-33-neutralizing recombinant ST2 receptor. Furthermore, IL-33 itself functions as an adjuvant that, while only inducing a marginal primary response, facilitates a robust secondary response comparable to that observed with alum. However, IL-33 is not absolutely required for alum-induced antibody responses since alum mediates similar humoral responses in IL-33 knockout and wild-type mice. Our results provide novel insights into the mechanism of action behind alum-induced cytokine responses and show that IL-33 is sufficient to provide a robust secondary antibody response independently of alum.

No MeSH data available.


Related in: MedlinePlus