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

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