Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products

Thirion-Delalande, Catherine; Gervais, Frédéríc; Fisch, C; Cuiné, Jean; Baron‐Bodo, Véronique; Moingeon, Philippe; Mascarell, Laurent

doi:10.1371/journal.pone.0183398

Cited by 43 publications

(37 citation statements)

References 45 publications

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“…In this study, canine sublingual epithelial cells were cultured as a monolayer. However, the sublingual epithelium consists of 12-18 layers in dogs (65). This difference might limit the conclusions that can be drawn for in vivo applications.…”

Section: Figure 3 |mentioning

confidence: 99%

“…Indeed, cytokine secretion repertoires of epidermal keratinocytes differed when cultured as a monolayer compared to a more complex multilayered culture model (39). Nevertheless, unlike the skin, the canine sublingual epithelium is non-keratinized tissue, which allows penetration of molecules to the level of the basal epithelial cells to exert their effects (37,65). This study therefore provides relevant insights into which mediators can be produced by sublingual epithelial cells positioned close to the basement membrane, mediators that could influence the behavior of local immune cells.…”

Section: Figure 3 |mentioning

confidence: 99%

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Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells

et al. 2020

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Application of allergens onto the sublingual epithelium is used to desensitize allergic individuals, a treatment known as sublingual immunotherapy. However, the response of sublingual epithelial cells to house dust mite allergen and potential tolerance-promoting adjuvants such as Toll-like receptor (TLR) ligands and calcitriol has not been investigated. In order to study this, primary sublingual epithelial cells were isolated from dogs and cultured in vitro. After 24-h incubation with a Dermatophagoides farinae extract, a Dermatophagoides pteronyssinus extract, TLR2 ligands (FSL-1, heat-killed Listeria monocytogenes, Pam3CSK4), a TLR3 ligand (poly I:C), a TLR4 ligand [lipopolysaccharide (LPS)], and calcitriol (1,25-dihydroxyvitamin D 3), viability of the cells was analyzed using an MTT test, and their secretion of interleukin 6 (IL-6), IL-10, CXCL8, and transforming growth factor β1 (TGF-β1) was measured by enzyme-linked immunosorbent assay. Additionally, to evaluate its potential effect as an adjuvant, sublingual epithelial cells were incubated with calcitriol in combination with a D. farinae extract followed by measurement of CXCL8 secretion. Furthermore, the effect of D. farinae and calcitriol on the transcriptome was assessed by RNA sequencing. The viability of the sublingual epithelial cells was significantly decreased by poly I:C, but not by the other stimuli. CXCL8 secretion was significantly increased by D. farinae extract and all TLR ligands apart from LPS. Calcitriol significantly decreased CXCL8 secretion, and coadministration with D. farinae extract reduced CXCL8 concentrations to levels seen in unstimulated sublingual epithelial cells. Although detectable, TGF-β1 secretion could not be modulated by any of the stimuli. Interleukin 6 and IL-10 could not be detected at the protein or at the mRNA level. It can be concluded that a D. farinae extract and TLR ligands augment the secretion of the proinflammatory chemokine CXCL8, which might interfere with sublingual desensitization. On the other hand, CXCL8 secretion was reduced by coapplication of calcitriol and a D. farinae extract. Calcitriol therefore seems to be a suitable candidate to be used as adjuvant during sublingual immunotherapy.

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Section: Figure 3 |mentioning

confidence: 99%

Section: Figure 3 |mentioning

confidence: 99%

Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells

et al. 2020

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“…The oral epithelium on the inferior tongue surface of rats is much thinner (8-12 layers) than that of humans (20-30 layers) with the same degree of rete ridge. 3,15 Previous research into cigarette smoke involving the use of Wistar rats has been carried out using three treatment methods, namely; inhalation exposure via the respiratory tract, whole body exposure, and nicotine injection. Nasal inhalation methods require oxygen masks, but these may be easily damaged by rats which belong to the rodent species.…”

Section: Discussionmentioning

confidence: 99%

Hyperplasia of Wistar rat tongue mucosa due to exposure to cigarette side-stream smoke

et al. 2019

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Background: Hyperplasia, a condition whereby an excessive number of cells are produced due to their uncontrolled division, represents a common symptom of carcinogenesis. Cancer is a physical manifestation of cell malignancy resulting from abnormal proliferation. Globally, oral cancer currently constitutes the sixth largest lethal form of the condition. The most common etiology of oral cancer is tobacco of which cigarettes are the most popular related product. The health risks associated with cigarette smoke not only affect active smokers but also individuals who ingest it passively. Sidestream smoke comes from the lighted end of a burning tobacco product such as a cigarette, pipe or cigar and contains nicotine and many harmful cancer-causing chemicals. Inhaling sidestream smoke increases the risk of lung and other types of cancer. Purpose: The purpose of this study was to understand how sidestream cigarette smoke initiates precancerous changes, in this case hyperplasia, in the oral mucosa epithelium of Wistar rats. Methods: The subjects were divided into three groups, a 4-week treatment group (P1), an 8-week treatment group (P2), and a control group (K), each consisting of ten subjects. The subjects were exposed to a daily two-cigarette dose of smoke. The experiment used a post-test only control group design. All samples were sacrificed during the fourth and eighth weeks. Haematoxylin-eosin staining was performed on the tongues of the Wistar rats to establish the presence of hyperplasia. Data was analyzed using a one-way ANOVA test. Results: After the Wistar rats had been exposed to cigarette smoke, an increased degree of epithelial cell proliferation (hyperplasia) showed a significant difference with a p-value <0.05 during the eighth week. Conclusion: Exposure to cigarette sidestream smoke induces increased epithelial cell proliferation (hyperplasia) in Wistar rats.

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“…Interestingly, a recent comparative study revealed that rodents and especially mice, could be used as animal models for pharmacodynamics/efficacy studies of SLIT [17]. Therefore, another goal of our investigation was to examine whether age and sex affect the efficacy of SLIT in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, immunological and morphologic functional evaluations of the oral mucosa are essential for further characterizing this mechanism. From an immunological point of view, several previous reports have suggested that antigen-presenting cells “APCs” (dendritic cells, macrophages) and regulatory T-cells in the sublingual mucosa play a role in antigen uptake and induction of immune tolerance following SLIT [13-17]. Furthermore, a recent report revealed the role of APCs in sublingual ductal epithelial cells in the transportation of sublingual antigen.…”

Section: Introductionmentioning

confidence: 99%

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

Elewa

Mizoguchi

Ichii

et al. 2018

Preprint

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Background24 Recently, sublingual immunotherapy (SLIT) has been used as a safe and efficient method for the 25 treatment of and immunization against asthma and various allergies. However, the routes of antigen 26 uptake through the mucosa of the oral cavity remain incompletely understood, as do the roles of sex 27 and age in the process. For this purpose, to elucidate the mechanism and efficacy of SLIT among 28 different sexes and ages microbeads were dripped into the sublingual region to mimic antigen uptake 29 by the sublingual mucosa.30 Methods 31 Twenty microliters of either phosphate buffered saline (PBS) or fluorescently labelled microbeads 32 (latex and silica beads) were placed under the tongue of both male and female C57BL/6 mice at young 33 (3 months) and old (6 months) ages. The lower jaw was examined 30 min after administration, and 34 beads were detected with a fluorescence stereomicroscope. Morphological observations of the 35 mucosa of the fluorescent areas were made with scanning electron microscopy (SEM) and an all-in-36 one light fluorescence microscope (LM). Fluorescence intensity was compared between both sexes 37 and ages.38 Results 39 Stereomicroscopic observation revealed fluorescent illuminations in three compartments of the 40 sublingual mucosa: the sublingual caruncles (SC), the oral rostral mucosa (OR) and the buccal 3 41 mucosa (BM). Interestingly, the fluorescence intensity tended to be higher among females than 42 among males in the SC region in particular. However, there were no significant age-related 43 differences. SEM and LM revealed beads in the lumina of both mandibular ducts and sublingual ducts 44 (Sd). Additionally, the apical cytoplasm of some Sd cells contained silica beads. However, there were 45 no specification in the OR mucosa or BM.46 Conclusions 47 This study reveals the major role Sd play in local immunity via the antigen uptake mechanisms.48 Furthermore, our data suggest that the efficacy of SLIT in humans could be affected by sex.49 Keywords: antigen uptake, beads, sublingual immunotherapy, sublingual caruncles, C57BL/6 mice 4 50 INTRODUCTION 51 In both humans and animals, the prevalence of allergic diseases such as seasonal rhinitis and atopic 52 dermatitis has increased substantially in recent decades [1][2][3]. The symptoms accompanying such 53 allergic conditions range in severity. Mild symptoms such as itching and sneezing may cause 54 disturbances in the patient's daily life and affect productivity, while severe ones such as anaphylactic 55 shock can be life-threatening [4]. Therefore, establishing countermeasures against the development 56 of allergic conditions is an important issue in both the medical and veterinary fields.57 Treatment for allergic diseases is currently based primarily on symptomatic therapy to reduce 58 inflammation; antihistamines and steroids are widely used for this [5, 6]. However, immune induction 59 therapy has attracted attention in recent years. Among them is sublingual immunotherapy (SLIT), 60 which is allergen-specific. In SLI...

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Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products

Cited by 43 publications

References 45 publications

Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells

Adjuvanting Allergen Extracts for Sublingual Immunotherapy: Calcitriol Downregulates CXCL8 Production in Primary Sublingual Epithelial Cells

Hyperplasia of Wistar rat tongue mucosa due to exposure to cigarette side-stream smoke

Morphofunctional analysis of antigen uptake mechanisms following sublingual immunotherapy with beads in mice

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