Humanized Mouse Models for the Study of Periodontitis: An Opportunity to Elucidate Unresolved Aspects of Its Immunopathogenesis and Analyze New Immunotherapeutic Strategies

Abstract

Periodontitis is an oral inflammatory disease in which the polymicrobial synergy and dysbiosis of the subgingival microbiota trigger a deregulated host immune response, that leads to the breakdown of tooth-supporting tissues and finally tooth loss. Periodontitis is characterized by the increased pathogenic activity of T helper type 17 (Th17) lymphocytes and defective immunoregulation mediated by phenotypically unstable T regulatory (Treg), lymphocytes, incapable of resolving the bone-resorbing inflammatory milieu. In this context, the complexity of the immune response orchestrated against the microbial challenge during periodontitis has made the study of its pathogenesis and therapy difficult and limited. Indeed, the ethical limitations that accompany human studies can lead to an insufficient etiopathogenic understanding of the disease and consequently, biased treatment decision-making. Alternatively, animal models allow us to manage these difficulties and give us the opportunity to partially emulate the etiopathogenesis of periodontitis by inoculating periodontopathogenic bacteria or by placing bacteria-accumulating ligatures around the teeth; however, these models still have limited translational application in humans. Accordingly, humanized animal models are able to emulate human-like complex networks of immune responses by engrafting human cells or tissues into specific strains of immunodeficient mice. Their characteristics enable a viable time window for the study of the establishment of a specific human immune response pattern in an in vivo setting and could be exploited for a wider study of the etiopathogenesis and/or treatment of periodontitis. For instance, the antigen-specific response of human dendritic cells against the periodontopathogen Porphyromonas gingivalis favoring the Th17/Treg response has already been tested in humanized mice models. Hypothetically, the proper emulation of periodontal dysbiosis in a humanized animal could give insights into the subtle molecular characteristics of a human-like local and systemic immune response during periodontitis and support the design of novel immunotherapeutic strategies. Therefore, the aims of this review are: To elucidate how the microbiota-elicited immunopathogenesis of periodontitis can be potentially emulated in humanized mouse models, to highlight their advantages and limitations in comparison with the already available experimental periodontitis non-humanized animal models, and to discuss the potential translational application of using these models for periodontitis immunotherapeutics.

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

“…In fact, oral administration of bacteria and local injection of lipopolysaccharide (LPS) or Porphyromonas gingivalis are also commonly used methods for establishing periodontitis in mice [13]. However, these two methods take a longer time (around four to six weeks) to produce a significant loss of periodontal tissue than the ligation method [14,15].…”

Abnormal Micronutrient Intake Is Associated with the Risk of Periodontitis: A Dose–response Association Study Based on NHANES 2009–2014

“…Periodontitis is a common chronic inflammatory condition that affects the tissues surrounding the teeth, leading to pocket formation, movement, bone loss, and eventually tooth loss [1][2][3]. In addition to its impact on periodontal tissues, periodontitis is closely associated with the progression of chronic diseases that pose substantial health and financial burden [4][5][6], including diabetes, hypertension, Alzheimer's disease, and coronary heart disease [7][8][9][10][11].…”

The Receptor AT1 Appears to Be Important for the Maintenance of Bone Mass and AT2 Receptor Function in Periodontal Bone Loss Appears to Be Regulated by AT1 Receptor

“…The technical procedure involves placing ligatures around a posterior tooth. Ligatures are believed to facilitate local bacterial accumulation and thus increase bacterial-mediated inflammation and bone loss [ 31 , 32 ]. The major limitation of the ligature-induced periodontitis in mice is due to the technical challenges related to the relatively small size of the oral cavity of these animals.…”