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

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-1 beta during an immune response could elicit polyclonal anti-IL-1 beta antibody responses that modulated IL-1 beta's in vivo activity. Methods: We engineered 2 different IL-1 beta 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-1 beta 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-1 beta, antibody responses induced by the other variant even potentiated the in vivo effects of IL-1 beta; the latter led to enhanced morbidity in 2 different IL-1 beta-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.