Table 4 A summary of immunotherapies and their targets
From: Advances in novel therapeutic approaches for periodontal diseases
Type of Therapy | Immunomodulatory activity on targets | References | |||
|---|---|---|---|---|---|
| Â | Monocytes/Macrophage | Lymphocyte | Cytokines | ||
Drug therapy | Resveratrol | Treatment of gingival keratinocytes with Resveratrol inhibited NF-kB activation and reduced the marker TREM-1 in monocytes | / | / | [107] |
Metformin | In Monocytes, metformin hindered the production of nitric oxide synthase and nitric oxide induced with LPS. In addition, this drug decreased the expression of chemokine (C–C motif) ligand 2 (CCL-2) to improve inflammation | / | Delivery of metformin in diabetic mice with periodontitis effectively decreased NLRP3 and IL-1β levels reducing inflammation | ||
Catechin | / | / | Catechin decreased IL-1β level from macrophages in mice model of gingivitis | [110] | |
Gliclazide | Gliclazide treatment in a rat model of periodontitis reduced infiltration of neutrophils, macrophages and reduced activity of myeloperoxidase enzyme | / | This drug also reduced inflammation by declining the levels of IL-1β and TNF-α, as well as reduced the expression of COX-2 and cathepsin k | [111] | |
Curcumin (CMC2.24) | Chemically-Modified version of Curcumin (CMC2.24) reduced phagocytic activity of macrophages | / | Also, curcumin reduced oxidative stress, bone resorption and inflammatory response by decreasing the levels of TNF-α, IL-1β, IL-10 | ||
Trans-cinnamic aldehyde | / | / | A. actinomycetemcomitans infected cells were pre-treated with trans-cinnamic aldehyde which lowered the levels of TNF-α, IL-1β | [115] | |
The Amyl-1–18 peptide | This peptide was derived from rice which can inhibit the secretion of IL-6 from macrophage |  | This peptide can also counteract LPS, suppress signal transduction in NF-kB as well as IL-1R signaling pathway | [200] | |
Kava-205Me | / | / | Addition of methyl group to natural compound kavain is known as Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate). Kavain is generally obtained from Piper methysticum Human cell lines were infected with P. gingivalis and treated with Kava-205Me at different doses. This compound could decrease the levels of IL-12, IL-10, IFN-γ and exotoxin. These cytokines indicate the early phase of inflammation | [201] | |
Carnosic Acid | Carnosic acid reduced infiltration of inflammatory cells | / | This phenolic diterpene which is a natural compound imparted anti-oxidative and anti-inflammatory properties in mice model challenged with LPS. Application of carnosic acid led to the decrease in expression of CXCL9, CXCL10, and CXCL11 | [202] | |
Glyburide | Glyburide is a blood sugar lowering drug. Treatment with glyburide declines infiltration of inflammatory cells and number of osteoclast cells | / | THP-1 which is a macrophage-like cell line was stimulated with periodontal pathogenic bacteria and treated with glyburide, which resulted in decrease of IL-1β levels in culture media but increase in expression of endogenous IL-1β | [116] | |
Bismuth drugs | / | / | Treatment of P. gingivalis challenged human cells with bismuth drugs decreased its iron acquisition ability and reduced the levels of proinflammatory cytokines such as IL-6, IL-1β and TNF-α | [117] | |
Gene therapy | T-cell immune response cDNA7 (TIRC7) Isoform of Atp6i | / | Downregulation of TIRC7 was achieved by shRNA and delivered locally by Adeno-Associated Virus (AAV). This modification of gene led to the lowering T cells in the gingival tissue | In addition, silencing of TIRC7 triggers the reduction in levels of IL-6, IL-17A and Cathepsin K (Ctsk) in periodontal tissue | [118] |
MicroRNA-200c (miR-200c) | / | / | Plasmid DNA encoding miR-200c was directly injected into the gingiva which rescued the downregulation of miR-200c as well as prevented periodontal inflammation. In addition, miR-200c effectively decreased the levels of IL-6 and IL-8 at transcription level which is involved in sustaining systemic inflammation in periodontitis | [119] | |
Ctsk | / | Ctsk was downregulated by shRNA and carried in AAV to deliver in periodontal ligament cells, which reduced the number of T cells and dendritic cells. This abolished inflammation and osteoclast activity | Silencing of Ctsk also decreased the levels of cytokines such as TNF-α, INF-γ, IL-1α, IL-1β, IL-12 and IL-17 while upregulates the levels of IL-6 in vivo | [120] | |
P2X7R | / | / | P2X7 receptor (P2X7R) gene-modified stem cells help to reduce inflammation. Moreover, this genetically modified cells ameliorate the harsh local microenvironment of periodontitis through secreting molecules on neighboring cells and improve tissue regeneration | [121] | |
TNFR: Fc | / | In rat model of periodontal disease, application of a fusion gene containing TNF receptor and immunoglobulin Fc (TNFR: Fc) by AAV increase the expression of TNFR protein in serum at therapeutic level. This protein also reduced infiltration of leukocytes at the site of infection | Moreover, TNFR protein decreased the levels of several cytokines such as IL-1β, TNF-α, IL-6 and IL-10 which reduced inflammation as well as prevented bone loss | [122] | |
Stem cell therapy | Periodontal ligament stem cells (PDLSCs) | Application of PDLSCs promote the conversion of macrophages to the anti-inflammatory (M2) phenotype which helps to enhanced regeneration of tissues | PDLSCs can suppress immune response by performing anergy of T-cell and decreasing the proliferation, differentiation and activation of B cells | Moreover, a significant amount of decrease in the level of glycoprotein named CD1b was observed on dendritic cells due to the application of PDLSCs. This stem cell therapy inhibited the proliferation of T cell suggesting a promising a novel therapeutic approach | |
Gingiva-Derived Mesenchymal Stem cells (GMSCs) | Extracellular vesicles obtained from GMSC promote the polarization of M1 to M2 macrophages | GMSCs can reduce the infiltration of neutrophils, Th17 cells, as well as increase the migration of Tregs | Application of GMSCs decreased pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 significantly while increases the anti-inflammatory cytokine IL-10 | ||
Mesenchymal stem cells derived from human exfoliated deciduous teeth (SHEDs) | Enhance the differentiation of anti-inflammatory macrophages | Promote an immunomodulatory function in monocyte derived from dendritic cells | Application of SHED at different dose showed a decrease in levels of TNF-α, IFN-γ and IL-2, and an increase in IL-10 showed in rat model | ||
Dental Follicle Stem Cells (DFSCs) | / | Increased the number of Tregs | When stimulated by IFN-γ, DFSCs can modulate peripheral blood mononuclear cells (PBMCs) obtained from healthy donor by enhancing the levels of IL-10 but decreasing the levels of IFN-γ and IL-4 DFSCs showed immune response to lipopolysaccharide (LPS) from P. gingivalis leading to decreased levels of TLR4 mRNA significantly. This was accompanied by an increased migration of the stem cells without altering the levels of IL-6 | ||
Bone Marrow Mesenchymal Stem Cells (BMMSCs) | Extracellular vesicles derived from BMMSCs decreased the levels of M1 macrophages and increased the levels of M2 macrophages | / | In periodontitis model of rat, transplantation of Acetylsalicylic acid treated BMMSCs increased IL-10 and reduced tumor necrosis factor-α (TNF-α) and IL-17 reducing inflammation In another study of rat model with periodontal disease, application of BMMScs showed reduction in levels of IL-1β, TNF-α,IL-17 | ||
Dental pulp stem cells (DPSCs) | Moreover, exosomes-incorporated in chitosan hydrogel obtained from DPSCs enhanced the conversion of proinflammatory state macrophages to an anti-inflammatory state | Increased the number of Tregs and decreased Th17 cells | LPS challenged co-culture of DPSCs and PBMCs showed decrease in TNF-α, IFN-γ, IL-2, IL-17 and an increase in IL-10 secretion without altering the levels of IL-6 and IL-1β | ||
Other therapy | Photodynamic therapy (PDT) | / | / | Decreased the levels of TNF-α in asthmatic animals challenged with P. gingivalis Decreased the level of IL-6, IL-8, and CXCL10 in A. actinomycetemcomitans and promotes periodontal regeneration | [211] [212] |
Methylene blue-mediated photodynamic therapy (MBPDT) | Induction of apoptosis in macrophage due to oxidative stress as well as mitochondria dependent apoptosis pathways were shown in vitro | / | Lower levels of IL-1β and TNF-α was observed | [213] | |
Low-intensity pulsed ultrasound (LIPUS) | / | / | Treatment suppressed a range of cytokines at transcription level including IL-1a, IL-1b, IL-6, IL-8 as well as reduced the levels of IL-1ß and tumor necrosis factor a (TNFα) by periodontal ligament fibroblasts (PDLFs) | [214] | |
Singlet phototherapy | Infiltration of macrophages in periodontitis and significant vascularization of periodontal tissue that contributed to tissue regeneration and ameliorate infection | / | / | [215] | |
Indocyanine green (ICG)-diode laser-based photothermal therapy (PTT) | / | / | Reduction of IL-1β and MMP-8 at 6 months after treatment in patients with gingival inflammation | [213] | |