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Endogenous polyclonal anti-IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation


Spohn, Gunther; Arenas-Ramirez, Natalia; Bouchaud, Gregory; Boyman, Onur (2017). Endogenous polyclonal anti-IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation. Journal of Allergy and Clinical Immunology, 139(6):1957-1965.e3.

Abstract

BACKGROUND Particular neutralizing mAbs to certain cytokines act as agonists in vivo through protection of the cytokine's active site and prolongation of its half-life. Although this principle might be useful for targeted immunotherapy, its role in the pathogenesis of inflammation and autoimmunity is unclear. OBJECTIVE We sought to determine whether slight, structurally nonrelevant modifications of the prototypic proinflammatory cytokine IL-1β during an immune response could elicit polyclonal anti-IL-1β antibody responses that modulated IL-1β's in vivo activity. METHODS We engineered 2 different IL-1β variants, thereby mimicking the process of cytokine modification occurring during inflammation, and conjugated them to virus-like particles, followed by immunization of mice. The resulting polyclonal anti-IL-1β antibody responses were assessed by using in vitro and in vivo assays, as well as 2 relevant (auto-) inflammatory murine models. RESULTS Although antibody responses generated to one variant were potently inhibiting IL-1β, antibody responses induced by the other variant even potentiated the in vivo effects of IL-1β; the latter led to enhanced morbidity in 2 different IL-1β-mediated mouse models, including a model of inflammatory bowel disease and an inflammatory arthritis model. CONCLUSION These data demonstrate that endogenous polyclonal anti-cytokine antibody responses can enhance the cytokine's activity in inflammatory and autoimmune diseases.

Abstract

BACKGROUND Particular neutralizing mAbs to certain cytokines act as agonists in vivo through protection of the cytokine's active site and prolongation of its half-life. Although this principle might be useful for targeted immunotherapy, its role in the pathogenesis of inflammation and autoimmunity is unclear. OBJECTIVE We sought to determine whether slight, structurally nonrelevant modifications of the prototypic proinflammatory cytokine IL-1β during an immune response could elicit polyclonal anti-IL-1β antibody responses that modulated IL-1β's in vivo activity. METHODS We engineered 2 different IL-1β variants, thereby mimicking the process of cytokine modification occurring during inflammation, and conjugated them to virus-like particles, followed by immunization of mice. The resulting polyclonal anti-IL-1β antibody responses were assessed by using in vitro and in vivo assays, as well as 2 relevant (auto-) inflammatory murine models. RESULTS Although antibody responses generated to one variant were potently inhibiting IL-1β, antibody responses induced by the other variant even potentiated the in vivo effects of IL-1β; the latter led to enhanced morbidity in 2 different IL-1β-mediated mouse models, including a model of inflammatory bowel disease and an inflammatory arthritis model. CONCLUSION These data demonstrate that endogenous polyclonal anti-cytokine antibody responses can enhance the cytokine's activity in inflammatory and autoimmune diseases.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Immunology
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cytokine, IL-1β, antibody, autoantibody, autoinflammatory disease, inflammation, inflammatory disease
Language:English
Date:2017
Deposited On:27 Jan 2017 12:12
Last Modified:19 Feb 2018 07:34
Publisher:Elsevier
ISSN:0091-6749
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jaci.2016.09.033
PubMed ID:27833025

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