Local Sustained Delivery of Anti–IL-17A Antibodies Limits Inflammatory Bone Loss in Murine Experimental Periodontitis

Abstract

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A–mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti–IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti–IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti–IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti–IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A–driven inflammation.

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

“…In a recent study, the expression of Il17a was moderated in the first two days after the periodontitis model was established but increased rapidly in the subsequent days. This study also suggested that anti-IL-17A Abs decreased IL-6 gene expression in gingival tissue of periodontitis-induced mice and suppressed alveolar bone loss and osteoclastic activity; hence, IL-17A Abs might be an effective treatment for periodontitis [152]. In a recent study, IL-10 was reported to act as a negative feedback regulator to inhibit excessive IL-17 activity.…”

Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chronic Inflammatory Diseases

“…At present, there are no clinical studies on IL-17A inhibitors for the treatment of periodontitis. In animal experiments, Pacheco recently found that continuous delivery of IL-17A neutralizing Antibodies in local periodontal region could limit inflammatory bone loss in experimental periodontitis mice ( 133 ). More research are needed to determine whether IL-17A inhibitors can be used topically to treat periodontitis and at what development stage of periodontitis that IL-17A inhibitors should be used.…”

Local induction of regulatory T cells prevents inflammatory bone loss in ligature-induced experimental periodontitis in mice

“…Specifically, it is not just the microbial dysbiosis but an underlying unbalanced host immune response that is ultimately responsible for the inflammatory destruction and disease progression of periodontitis 20 , 21 . This renewed understanding has made way for a multitude of new immunomodulatory approaches as potential treatments; from the use of pro-resolving molecules like lipoxins and resolvins 22 to strategies of modulating innate immune cells such as macrophages 23 and cytokine signaling such as Del-1 or anti-IL17 24 , 25 . Therefore, in this study, we evaluated the effect of re-balancing the host immune response through an immune cell modulation strategy of locally inducing regulatory T cells (Tregs) for its impact on inflammatory bone loss in periodontitis.…”