|Year : 2015 | Volume
| Issue : 2 | Page : 49-52
Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases
Tsuyoshi Sato1, Michihiko Usui2, Yuichiro Enoki1, Shoichiro Kokabu3, Tetsuya Yoda1
1 Department of Oral and Maxillofacial Surgery, Saitama Medical University, Saitama, Japan
2 Division of Periodontology, Department of Oral Function, Kyushu Dental University, Fukuoka, Japan
3 Division of Molecular Signaling and Biochemistry, Department of Health Promotion, Kyushu Dental University, Fukuoka, Japan
|Date of Web Publication||10-Jun-2015|
Dr. Tsuyoshi Sato
Department of Oral and Maxillofacial Surgery, Saitama Medical University, 38 Moro-hongou, Moroyama-machi, Iruma-gun, Saitama - 350-0495
Source of Support: None, Conflict of Interest: None
Introduction: Recurrent aphthous stomatitis and oral lichen planus are local chronic inflammatory diseases which are implicated in T cell-mediated immunity. According to the systematic review, there is insufficient evidence to support any specific treatment for T-cell mediated oral diseases. The hypothesis: In this paper, we propose a hypothesis that recurrent aphthous stomatitis and oral lichen planus can be treated with selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR) agonists. Our hypothesis is supported by the following two facts. First, the pathophysiological conditions, T h 1/T h 17 cell activation and autonomic nervous system dysfunction, are observed in T-cell mediated oral diseases as well as in T-cell mediated systemic diseases such as rheumatoid arthritis. Second, the cholinergic anti-inflammatory pathway is inhibited in systemic T-cell mediated chronic inflammatory diseases. On the other hand, treatment with α7 -nAChR agonists which activate the cholinergic anti-inflammatory pathway suppresses neuroinflammation via inhibition of T h 1/T h 17 responses in animal model of systemic T-cell mediated chronic inflammatory diseases. We thus expect that selective α7 -nAChR agonists will be effective for the treatment of T-cell mediated oral diseases. Evaluation of the hypothesis: To test our hypothesis, we need to develop in vivo mouse model of T-cell mediated oral diseases. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we choose ABT-107 because of its safety and tolerability. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat T-cell mediated oral diseases.
Keywords: Autonomic nervous system dysfunction, oral lichen planus (OLP), recurrent aphthous stomatitis (RAS), selective α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR) agonists, T helper 1/T helper 17 (T h 1/T h 17) cell activation, the cholinergic anti-inflammatory pathway
|How to cite this article:|
Sato T, Usui M, Enoki Y, Kokabu S, Yoda T. Possible neuroimmunomodulation therapy in T-cell-mediated oral diseases. Dent Hypotheses 2015;6:49-52
| Introduction|| |
Recurrent aphthous stomatitis (RAS) and oral lichen planus (OLP) are local chronic inflammatory diseases, which are implicated in T-cell-mediated immunity. 
RAS is characterized by multiple recurrent round painful ulcers accompanying an erythematous halo. Although the etiology of RAS is unknown, several causative factors such as immunologic, genetic, allergic, nutritional, and microbial factors have been proposed.  The most widely used drugs for the treatment of RAS are the topical corticosteroids. Antiseptics and anti-inflammatory drugs, such as 0.2% chlorhexidine in the form of rinses or gel, are also used. However, in the comprehensive systematic review, no single treatment was found to be effective in the reduction of pain associated with RAS. 
OLP exhibits several different clinical patterns. Among them, the two main types, i.e., reticular type and erosive type are common lesions.  Although the etiology of OLP is uncertain, accumulating evidence suggests that an immune-mediated mechanism is involved in developing the disease. Topical steroids in adhesive bases are widely used for the treatment of OLP. According to the systematic review, however, there is insufficient evidence to support any specific treatment for OLP as being superior. 
Both RAS and OLP are inflammatory diseases associated with T-cell-mediated immunity. T h 1 immune response is activated by these diseases. , Accumulating evidence suggests that T h 17, which can produce interleukin-17 (IL-17) and IL-22 and is associated with inflammatory disorders,  is implicated in the pathogenesis of these diseases. Serum IL-17 levels are higher in RAS patients than in healthy controls.  High levels of IL-17 are produced by CD4 + T cell clones from OLP as compared with control.  T h 1 and T h 17 cells are considered pathogenic T cells that activate the inflammatory process in chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis.  Using a neutralizing antibody to target the endogenous cytokines is considered an effective treatment for these inflammatory diseases.  Biologic immunomodulatory agents are also useful for the management of RAS and OLP, but their use is off-label.  On the other hand, biologic therapy is more expensive than traditional treatment. 
Gavic and coworkers proposed that anxiety, depression, and stress are involved in the symptoms of RAS and OLP.  Their study demonstrated that the psychological profiles of patients strongly correlate to such symptoms. Other studies have also reported significant associations between the symptoms and psychological stress in these diseases. ,, The hypothalamic-pituitary-adrenal axis and the autonomic nervous system play major roles in maintaining the stress response.  Psychological stress disrupts homeostasis among the organs, and autonomic nervous system dysfunction has a critical role in stress-related disorders.  Several studies have shown elevated levels of inflammatory biomarkers in patients with depression, suggesting that psychological stress is related to inflammation. ,
Recent seminal studies have demonstrated a relation between neuroscience and immunology.  A neural circuit, designated as the "cholinergic anti-inflammatory pathway," is mediated by the vagus nerve. Stimulation of the vagus nerve reduces proinflammatory cytokine production via the α7 subunit of nicotinic acetylcholine receptor (α7 -nAChR) on cytokine-producing cells ex vivo. Activation of this pathway by the administration of selective α7 -nAChR drugs that suppress cytokine production is expected to effectively ameliorate inflammatory diseases. For example, although the amount of cytokine release in the whole blood organ culture stimulated by endotoxin was significantly lower in patients with RA than in controls, the reduction in cytokine levels remained significantly greater after exposure to α7 -nAChR agonists in the controls as compared with the RA patients.  Moreover, physiological studies of these patients revealed reduced vagus nerve activity. In line with this, autonomic nervous system dysfunction is found in RA patients, and psychological stress is a risk factor for the development of RA.  We speculate that disruption of the cholinergic anti-inflammatory pathway due to autonomic nervous system dysfunction may be involved at the onset or duration of RAS and OLP [Figure 1].
Intriguingly, treatment with α7 -nAChR agonists suppresses neuroinflammation via inhibition of T helper 1/T helper 17 (T h 1/T h 17) responses in vivo.  The study demonstrated that α7 -nAChR is expressed by CD4 + T cells and that this expression is upregulated following T cell activation. Nicotine, which activates α7 -nAChR, decreased the reactivity of the T h 1 and T h 17 lineages, including reduced specific cytokine production. This finding supports the notion that activation of α7 -nAChR may be an effective treatment for T-cell-mediated inflammatory diseases. These facts led us to develop a new idea, namely, neuroimmunomodulation therapy using selective α7 -nAChR agonists for the treatment of RAS and OLP.
| The Hypothesis|| |
We propose a hypothesis that RAS and OLP can be treated with selective α7 -nAChR agonists, which are considered the therapeutic agents for central nervous system disorders [Figure 2]. Additionally, the production costs may be lower than those of biologic immunomodulatory agents.
|Figure 2: Proposed treatment for RAS and OLP by the administration of selective α7-nAChR|
Click here to view
| Evaluation of the Hypothesis|| |
To test our hypothesis, we needed to develop in vivo mouse model of T-cell-mediated oral diseases. Referring to the protocol by Oz et al., trinitrobenzenesulfonic acid (TNBS) was injected into the buccal mucosa of mice,  because TNBS causes an inflammatory immune response.  In order to explore the direct effect of local TNBS delivery into the buccal mucosa, 50 μL TNBS was inoculated via a 28-gauge hypodermic needle into the right side, and the left side was injected with a vehicle control. To evaluate the therapeutic effect of a selective α7 -nAChR agonist, we chose 5-(6-[(3R)-1-azabicyclo [2, 2, 2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107) because of its safety and tolerability.  ABT-107 (0.1 μmol/kg and 10 μmol/kg) or a vehicle was intraperitoneally injected twice a week before the date of sacrifice.  Referring to the protocol by Nizri et al., the presence of interferon gamma (IFNγ), tumor necrosis factor-α (TNF-α), IL-17, IL-4, and IL-10 were determined in the culture media of lymphocytes incubated in the presence of myelin oligodendrocyte glycoprotein (MOG35-55), using an enzyme-linked immunosorbent assay (ELISA) kit.  These experiments will clarify whether neuroimmunomodulation therapy by the activation of α7 -nAChR via suppression of T h 1/T h 17 is an effective treatment for T-cell-mediated oral diseases.
We strongly expect that selective α7 -nAChR agonists will be used in the therapy of RAS and OLP. Indeed, nicotine, which is one of the α7 -nAChR agonists, is effective for the treatment of oral ulcers. For instance, nicotine replacement therapy has been effective in treating recurrent aphthous ulcers after smoking cessation  and therapy with a nicotine patch led to a regression of all aphthous ulcers associated with Behçet's syndrome. 
Because selective α7 -nAChR agonists are synthetic compounds, the production costs may be lower than those of biologic immunomodulatory agents. Although several α7 -nAChR agonists have been recently described, most have inherent limitations.  Some compounds have relatively high affinity for other receptors, resulting in unnecessary pharmacological effects. Among them, however, ABT-107 is considered a candidate selective α7 -nAChR agonist as a therapeutic agent.  This compound has a high affinity for the human α7 -nAChR and may have therapeutic potential in Alzheimer's disease symptomatic alleviation.  According to the previous clinical study, adverse events such as nausea, headache, and tremor were mild in severity.  To reduce the adverse effect, development of topical agents, such as ointments, is needed. We believe that the selective α7 -nAChR agonist, especially ABT-107, may be a therapeutic drug to treat RAS and OLP.
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[Figure 1], [Figure 2]