Endogenous polyclonal anti–IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation Gunther Spohn, PhD, Natalia Arenas-Ramirez,

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Presentation transcript:

Endogenous polyclonal anti–IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation Gunther Spohn, PhD, Natalia Arenas-Ramirez, PhD, Gregory Bouchaud, PhD, Onur Boyman, MD Journal of Allergy and Clinical Immunology Volume 139, Issue 6, Pages 1957-1965.e3 (June 2017) DOI: 10.1016/j.jaci.2016.09.033 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2017 139, 1957-1965 Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Generation of different endogenous polyclonal anti–IL-1β antibody responses. A, Three-dimensional structure of the IL-1β−IL-1RI complex (accession code 3O4O),48 showing the different IL-1R interaction sites of IL-1β. B, Groups of C57BL/6 mice (n = 4) were immunized on days 0, 14, and 28 with 25 μg of Qβ-hIL-1b(R11G), Qβ-hIL-1b(D145K), or Qβ-VLPs as a control. Wild-type (WT) hIL-1β–specific total IgG ELISA titers were measured in sera collected 25 days after the last immunization. C, Neutralizing antibody titers were determined by incubating HeLa cells with serial dilutions of the same sera as in Fig 1, B, which had been premixed with a constant amount of WT hIL-1β. D, Serial dilutions of the same sera as in Fig 1, B, were applied to hIL-1β–His-C captured on Ni2+-coated plates (C-terminal capture) or to WT hIL-1β captured on gevokizumab-coated ELISA plates. Shown are group means ± SEMs from one of 2 experiments with similar results. Dashed lines indicate detection limits. P values were determined by using 1-way ANOVA with the Tukey multiple comparison test. n.s., Not significant. *P < .05 and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Modulation of hIL-1β activity by Qβ–IL-1β mutein-induced antibodies. Groups of C57BL/6 mice (n = 4) were immunized as in Fig 1, followed by an intraperitoneal injection of 1 μg of WT hIL-1β. Serum levels of human IL-1β (A) and mouse IL-6 (B) were measured 3 and 6 hours after the challenge. Shown are group means ± SEMs of pooled data from 2 experiments performed under the same conditions. Dashed lines indicate detection limits of IL-1β (20 pg/mL) and IL-6 (40 pg/mL) quantification assays. P values were determined by using 1-way ANOVA with the Tukey multiple comparison test. n.s., Not significant. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Qβ–IL-1β mutein-induced antibodies show different IL-1β neutralizing abilities. Groups of C57BL/6 mice (n = 2-3) were immunized on days 0, 14, and 28 with 10 to 15 μg of the indicated Qβ–hIL-1β mutein conjugates (A) or Qβ–mIL-1β mutein conjugates (B) or Qβ-VLPs as a control. Neutralizing activities of sera from immunized mice were determined by their ability to inhibit hIL-1β (Fig 3, A)– or mIL-1β (Fig 3, B)–stimulated IL-6 release by HeLa cells. Shown are group means ± SEMs of 3 independent experiments. P values were determined by using 2-way ANOVA with Bonferroni posttest correction. n.s., Not significant. ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Endogenous polyclonal anti–IL-1β antibodies exacerbate murine inflammatory arthritis. Groups of mice (n = 8) were immunized with the indicated Qβ-mIL-1β mutein conjugates or Qβ-VLPs as a control and injected with collagen in adjuvant to induce joint inflammation. Mice were examined daily, clinical scores ranging from 0 to 3 were assigned to each limb (A), and body weights were recorded (B). Shown are group means ± SEMs of one of 2 experiments with similar results. P values were determined by using 2-way ANOVA with Bonferroni posttest correction. P values were less than .0001 (Qβ-mIL-1b[D143K] vs Qβ; days 71-77), less than .1 (Qβ-mIL-1b[R10G] vs Qβ; days 55-61), .29 (Qβ-mIL-1b[D143K] vs Qβ; days 55-77), or .03 (Qβ-mIL-1b[R10G] vs Qβ; days 55-61). Time points at which mean clinical scores and body weight significantly differed from the Qβ control group are indicated. *P < .05, **P < .01, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Endogenous polyclonal anti–IL-1β antibody responses influence inflammatory bowel disease in vivo. A-C, C57BL/6 mice (n = 5) were immunized with Qβ-VLPs, Qβ-mIL-1b(R10G), or Qβ-mIL-1b(D143K), as in Fig 4, followed by induction of colitis with DSS and measurement of body weight (Fig 5, A). Two mice immunized with Qβ-mIL-1b(R10G) were found dead on day 9, as indicated. Representative hematoxylin and eosin staining of the colon (Fig 5, B), with scale bars representing 200 μm, and calculation of histologic scores (Fig 5, C) was performed on day 9 of DSS administration. Shown are groups means ± SEMs of pooled data of 2 experiments with similar results. P values were determined by using 1-way ANOVA with Bonferroni posttest correction. n.s., Not significant. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 IL-1R binding and IL-1β bioactivity of the hIL-1β muteins hIL-1b(R11G) and hIL-1b(D145K). A and B, ELISA plates were precoated with either IL-1RI (Fig E1, A) or IL-1RII (Fig E1, B), followed by incubation with titrated amounts of either hIL-1b(R11G), hIL-1b(D145K), or hIL-1β carrying the same N-terminus as the 2 muteins (MDI–hIL-1β); the hIL-1β constructs had been premixed with a constant amount of C-terminally biotinylated hIL-1β–His-C. Shown is receptor-bound biotinylated hIL-1β–His-C detected by using streptavidin-conjugated horseradish peroxidase. C, In vitro bioactivity of hIL-1β constructs was determined by incubating HeLa cells with titrated amounts of wild-type IL-1β or the indicated hIL-1β muteins and measurement of IL-6 release by HeLa cells in the supernatant by means of ELISA, with OD450nm values corresponding to the amount of IL-6. D, In vivo activity of hIL-1β constructs was assessed by injecting C57BL/6 mice (n = 4 per group) intraperitoneally with 1 μg of wild-type hIL-1β, hIL-1b(R11G), or hIL-1b(D145K), followed by measuring serum IL-6 levels 3 hours later by using a sandwich ELISA (detection limit, 20 pg/mL). Shown are group means ± SEMs. Statistical significance of differences was assessed by using 1-way ANOVA and the Tukey multiple comparison test. *P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Gevokizumab competes for hIL-1β binding with antibodies induced by hIL-1b(R11G) but not with antibodies induced by hIL-1b(D145K). Nickel plates were coated with His-tagged hIL-1β (5 μg/mL), followed by incubation with PBS (indicated by a minus symbol [−]) or gevokizumab (at 500 nmol/L [top] or 1 μmol/L [bottom]; indicated by a plus symbol [+]) and serum of mice immunized with either Qβ (black squares), Qβ-hIL-1b(R11G) (blue circles), or Qβ-hIL-1b(D145K) (red diamonds), as indicated. Mouse IgG was detected by using anti-mouse IgG antibody, indicating the presence of His-tagged hIL-1β–bound anti–hIL-1β antibodies. Detection of mouse IgG was at background levels in serum of mice immunized with Qβ. Data are presented as means ± SEMs (n = 3 sera of different mice of 2 independent experiments [ie, one using 500 nmol/L and another using 1 μmol/L gevokizumab, both showing comparable results]). P values were calculated with the unpaired Student t test. n.s., Not significant. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 1957-1965.e3DOI: (10.1016/j.jaci.2016.09.033) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions