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Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry.

Williams GR, Fierens K, Preston SG, Lunn D, Rysnik O, De Prijck S, Kool M, Buckley HC, Lambrecht BN, O'Hare D, Austyn JM - J. Exp. Med. (2014)

Bottom Line: Using a systems vaccinology approach, we find that every measured response can be modeled using a subset of just three physical and chemical properties for all compounds tested.This correlation can be reduced to a simple linear equation that enables the immunological responses stimulated by newly synthesized LDHs to be predicted in advance from these three parameters alone.This study demonstrates that immunity can be determined purely by chemistry and opens the possibility of rational manipulation of immunity for therapeutic purposes.

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Affiliation: Chemistry Research Laboratory, Department of Chemistry; Nuffield Department of Surgical Sciences, John Radcliffe Hospital; and Department of Statistics; University of Oxford, Oxford OX1 2JD, England, UKChemistry Research Laboratory, Department of Chemistry; Nuffield Department of Surgical Sciences, John Radcliffe Hospital; and Department of Statistics; University of Oxford, Oxford OX1 2JD, England, UK.

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Chemically different LDHs have distinct adjuvant activities in vivo. Mice were immunized i.p. with 10 µg OVA admixed with 1 mg LDH, Alhydrogel, or Imject alum and boosted i.p. 10 d later with 10 µg OVA alone. Control mice were given the booster treatment only. (a) 7 d after boost, mice were bled via the tail vein, and serum levels of OVA-specific antibody isotypes were measured by ELISA. (b) Starting 1 wk later, the prime-boosted mice were challenged on three consecutive days with a 1% OVA aerosol. 1 d after the final challenge, ELISA was used to measure serum levels of OVA-specific antibody isotypes. Antibody titers are shown as OD450, as assessed by ELISA. Error bars depict one standard error. **, P < 0.01 via pairwise comparisons versus OVA alone. Data are from two independent experiments, each with at least five mice per group.
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fig4: Chemically different LDHs have distinct adjuvant activities in vivo. Mice were immunized i.p. with 10 µg OVA admixed with 1 mg LDH, Alhydrogel, or Imject alum and boosted i.p. 10 d later with 10 µg OVA alone. Control mice were given the booster treatment only. (a) 7 d after boost, mice were bled via the tail vein, and serum levels of OVA-specific antibody isotypes were measured by ELISA. (b) Starting 1 wk later, the prime-boosted mice were challenged on three consecutive days with a 1% OVA aerosol. 1 d after the final challenge, ELISA was used to measure serum levels of OVA-specific antibody isotypes. Antibody titers are shown as OD450, as assessed by ELISA. Error bars depict one standard error. **, P < 0.01 via pairwise comparisons versus OVA alone. Data are from two independent experiments, each with at least five mice per group.

Mentions: To explore the potential in vivo adjuvant activities of LDHs, we next evaluated the capacity of some of our compounds to elicit antibody responses in C57BL/6 mice, based on a vaccination protocol to study adjuvant-driven responses against the model antigen OVA. Mice were primed i.p. with OVA admixed with each LDH, or alum, and boosted i.p. with soluble OVA 1 wk later (Eisenbarth et al., 2008; Kool et al., 2008b). Because this leads to primary antigen presentation in the mediastinal lymph nodes, which also drain the lungs, we then challenged the mice with a final, intranasal boost of soluble OVA 1 wk later. The resultant data confirmed that chemically different LDHs can elicit in vivo antibody responses that are at least as potent as those of the alums tested (Fig. 4 and Tables S7 and S8). Notably, vaccination with alum adjuvants resulted in OVA-specific IgG1 and IgE antibody production alone, reflective of a Th2-dominated response as expected, whereas some LDH compounds (e.g., Mg2Fe-CO3) stimulated production of OVA-specific IgG2c antibodies, indicative of a Th1-polarized response (Gavin et al., 2006; Eisenbarth et al., 2008). We then applied our regression model (above) to all of these in vivo antibody datasets and found that these, too, were very highly correlated with the same subset of LDH properties as above, conforming to Eq. 1. (Values for the properties and coefficients are shown in Tables S4 and S9.)


Immunity induced by a broad class of inorganic crystalline materials is directly controlled by their chemistry.

Williams GR, Fierens K, Preston SG, Lunn D, Rysnik O, De Prijck S, Kool M, Buckley HC, Lambrecht BN, O'Hare D, Austyn JM - J. Exp. Med. (2014)

Chemically different LDHs have distinct adjuvant activities in vivo. Mice were immunized i.p. with 10 µg OVA admixed with 1 mg LDH, Alhydrogel, or Imject alum and boosted i.p. 10 d later with 10 µg OVA alone. Control mice were given the booster treatment only. (a) 7 d after boost, mice were bled via the tail vein, and serum levels of OVA-specific antibody isotypes were measured by ELISA. (b) Starting 1 wk later, the prime-boosted mice were challenged on three consecutive days with a 1% OVA aerosol. 1 d after the final challenge, ELISA was used to measure serum levels of OVA-specific antibody isotypes. Antibody titers are shown as OD450, as assessed by ELISA. Error bars depict one standard error. **, P < 0.01 via pairwise comparisons versus OVA alone. Data are from two independent experiments, each with at least five mice per group.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
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fig4: Chemically different LDHs have distinct adjuvant activities in vivo. Mice were immunized i.p. with 10 µg OVA admixed with 1 mg LDH, Alhydrogel, or Imject alum and boosted i.p. 10 d later with 10 µg OVA alone. Control mice were given the booster treatment only. (a) 7 d after boost, mice were bled via the tail vein, and serum levels of OVA-specific antibody isotypes were measured by ELISA. (b) Starting 1 wk later, the prime-boosted mice were challenged on three consecutive days with a 1% OVA aerosol. 1 d after the final challenge, ELISA was used to measure serum levels of OVA-specific antibody isotypes. Antibody titers are shown as OD450, as assessed by ELISA. Error bars depict one standard error. **, P < 0.01 via pairwise comparisons versus OVA alone. Data are from two independent experiments, each with at least five mice per group.
Mentions: To explore the potential in vivo adjuvant activities of LDHs, we next evaluated the capacity of some of our compounds to elicit antibody responses in C57BL/6 mice, based on a vaccination protocol to study adjuvant-driven responses against the model antigen OVA. Mice were primed i.p. with OVA admixed with each LDH, or alum, and boosted i.p. with soluble OVA 1 wk later (Eisenbarth et al., 2008; Kool et al., 2008b). Because this leads to primary antigen presentation in the mediastinal lymph nodes, which also drain the lungs, we then challenged the mice with a final, intranasal boost of soluble OVA 1 wk later. The resultant data confirmed that chemically different LDHs can elicit in vivo antibody responses that are at least as potent as those of the alums tested (Fig. 4 and Tables S7 and S8). Notably, vaccination with alum adjuvants resulted in OVA-specific IgG1 and IgE antibody production alone, reflective of a Th2-dominated response as expected, whereas some LDH compounds (e.g., Mg2Fe-CO3) stimulated production of OVA-specific IgG2c antibodies, indicative of a Th1-polarized response (Gavin et al., 2006; Eisenbarth et al., 2008). We then applied our regression model (above) to all of these in vivo antibody datasets and found that these, too, were very highly correlated with the same subset of LDH properties as above, conforming to Eq. 1. (Values for the properties and coefficients are shown in Tables S4 and S9.)

Bottom Line: Using a systems vaccinology approach, we find that every measured response can be modeled using a subset of just three physical and chemical properties for all compounds tested.This correlation can be reduced to a simple linear equation that enables the immunological responses stimulated by newly synthesized LDHs to be predicted in advance from these three parameters alone.This study demonstrates that immunity can be determined purely by chemistry and opens the possibility of rational manipulation of immunity for therapeutic purposes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Chemistry Research Laboratory, Department of Chemistry; Nuffield Department of Surgical Sciences, John Radcliffe Hospital; and Department of Statistics; University of Oxford, Oxford OX1 2JD, England, UKChemistry Research Laboratory, Department of Chemistry; Nuffield Department of Surgical Sciences, John Radcliffe Hospital; and Department of Statistics; University of Oxford, Oxford OX1 2JD, England, UK.

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