Immunomodulation in the Treatment of Periodontitis: Progress and Perspectives

Abstract

Periodontitis is one of the most common dental diseases. Compared with healthy periodontal tissues, the immune microenvironment plays the key role in periodontitis by allowing the invasion of pathogens. It is possible that modulating the immune microenvironment can supplement traditional treatments and may even promote periodontal regeneration by using stem cells, bacteria, etc. New anti-inflammatory therapies can enhance the generation of a viable local immune microenvironment and promote cell homing and tissue formation, thereby achieving higher levels of immune regulation and tissue repair. We screened recent studies to summarize the advances of the immunomodulatory treatments for periodontitis in the aspects of drug therapy, microbial therapy, stem cell therapy, gene therapy and other therapies. In addition, we included the changes of immune cells and cytokines in the immune microenvironment of periodontitis in the section of drug therapy so as to make it clearer how the treatments took effects accordingly. In the future, more research needs to be done to improve immunotherapy methods and understand the risks and long-term efficacy of these methods in periodontitis.

Keywords: drug therapy; gene therapy; immune microenvironment (IME); immunomodulation; microbial therapy; periodontitis; stem cell therapy.

Figure 1

Immunotherapies of periodontitis. The above is a detailed classification of periodontitis immunotherapy, including drug therapy, microbial therapy, stem cell therapy, gene therapy, and other therapies. They are followed by more detailed classifications. PDLSCs, periodontal ligament stem cells; GMSCs, gingival mesenchymal stem cells; MSCs, mesenchymal stem cells; PT, periodontal therapy; PDT, photodynamic therapy; ICG, indocyanine green; PTT, photothermal therapy; MB-PDT, methylene blue-mediated photodynamic therapy; LIPUS, low-intensity pulsed ultrasound.

Figure 2

Drugs targeting neutrophils. Resveratrol, quercetin, and NAC can reduce the production of ROS by neutrophils, therefore contributing to the integrity of gingival tissues and prevention of periodontitis (41). Ascorbic acid can reduce inflammation in patients with periodontitis possibly because it usually acts as a reducing agent and can be used to treat periodontitis by reducing the extracellular oxidants of neutrophils (42, 43). APM is effective in inhibiting IL-8 production and decreasing cell damage through the suppression of intracellular ROS (44). ↑ is a symbol for positive effects, and ↓ is a symbol for negative effects and the same goes for the figures and tables below. NAC, N-acetylcysteine; ROS, reactive oxygen species; APM, L-Ascorbic acid 2-phosphate magnesium salt.

Figure 3

Drugs targeting macrophages. PSRE and PACN can decrease IL-8 and PGE2 by lipopolysaccharide-induced fibroblasts and IL-6 by leukocytes, blocking the expression of CD80 and CD86 on the surface of macrophages and IL-1 and COX-2 in leukocytes (64). PAC can protect macrophages against the cytotoxic effect of purified LtxA, reducing caspase-1 activation in LtxA-treated macrophages, consequently decreasing the release of IL-1β and IL-18. PACs can also neutralize the cytolytic and pro-inflammatory responses of human macrophages treated with LtxA. In addition, highbush blueberry PACs can also inhibit the secretion of IL-6, CXCL8, TNF-α, MMP-3, MMP-9, and sTREM-1in a dose-dependent manner (57, 65). PSRE, Pelargonium sidoides DC root extract; PACN, Proanthocyanidins; PAC, Proanthocyanidins.

Figure 4

Drugs targeting T lymphocytes and their mechanisms. Curcumin and calcitriol can regulate the differentiation of Th cells, thus playing a therapeutic role. Both of them can inhibit the loss of alveolar bone by changing the proportion and function of Th cell subsets, which is manifested by the increase of Treg cells and the decrease of Th17 cells. Calcitriol intervention can also increase Th2 polarization potential and decrease Th1 promoter (97, 98). In addition, curcumin also exerts antibacterial and antioxidanteffects (99, 100). AsIV can increase peripheral blood CD4(+)T cell percentages and the CD4(+)CD8/CD8(+) T-cell ratio, while the percentage of CD8(+) T cells can be significantly reduced, as well as TNF-α, IL-1β, IL-2, IgA and IgG (96). AsIV, Astragaloside IV.

Figure 5

Influence of vaccination against pathogens in patients and healthy people. P. gingivalis capsular defect mutant strains cause reduced loss of alveolar bone because of non-expression of RANKL and a decrease in Th1/Th17 cytokines, Th1/Th17 lymphocytes, and osteoclasts (156). Subcutaneously vaccination with formalin-killed P. gingivalis can result in upregulation of Tregs through the production of IL-10 and TGF-β, downregulation of Th17 cells and IL-17A production and inhibition of lymphocyte proliferation (157). P. gingivalis-specific inflammatory immune responses can be protected by therapeutic vaccination with a chimera (KAS2-A1) immunogen targeting the major virulence factors of the bacterium, the gingipain proteinases. This protection is characterized by an antigen-specific IgG1 isotype antibody and Th2 cell response (158). Patients with P. gingivalis-associated periodontitis have higher threshold levels of pathogens in the subgingival plaque and exhibit an inflammatory immune response. Therefore, therapeutic vaccination may exacerbate inflammation and bone resorption in these patients (89, 94).