Induction Of Mucosal Tolerance Research Articles

Mucosal tolerance induction in autoimmune myocarditis and myocardial infarction

BackgroundAntigen-specific therapy is a compelling approach for the treatment of autoimmune conditions. Primary goal is to induce the specific tolerization of self-reactive immune cells without altering host immunity against pathogens. We studied the effects of mucosal tolerance induction on cTnI-induced experimental autoimmune myocarditis (EAM) and post-infarct remodeling. MethodsMucosal tolerance was induced by intranasal application of cTnI, alternatively anti-CD3 p.o. Protocols varied in frequency, dosage and time point of application before EAM. We then applied the most effective regimen to mice undergoing myocardial infarction in order to verify its effectiveness in post-infarct cardiac remodeling. The myocardium was evaluated on histological slides and for the cytokine secretion pattern, while echocardiography determined cardiac function. ResultsA single dose of 100μg of cTnI 7days prior to myocarditis appeared to be most effective in suppressing inflammation and fibrosis (p=0.03), while improving fractional shortening (p=0.02). Treatment with intranasal cTnI upregulated IL-10 expression. On the other hand, frequent intranasal application of high doses of cTnI increased myocardial inflammation. Anti-CD3 p.o. showed the propensity to reduce myocardial inflammation and improve cardiac function. The single dose regimen of i.n. cTnI applied 7days before a myocardial infarction reduced inflammation by trend (p=0.07) and improved heart function (p=0.002). Moreover, expression of matrix metalloproteinases 9 and 14 significantly decreased when treated with intranasal cTnI (p<0.01). ConclusionsDepending on the optimal amount, the time period and the choice of antigen, effective mucosal tolerance can be achieved and represents an appealing therapeutic approach in the inflammatory process of cardiac remodeling.

Oral tolerance

Summary: The gut‐associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T‐cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103+ retinoic acid‐dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor‐β dependent and express latency‐associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin‐10 dependent) are induced by nasal antigen and forkhead box protein 3+ iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti‐CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti‐CD3 monoclonal antibody induces LAP+ Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non‐toxic, physiologic approach to reach this goal.

Modulation of Human Immune Responses by Bovine Interleukin-10

Cytokines can be functionally active across species barriers. Bovine IL-10 has an amino acid sequence identity with human IL-10 of 76.8%. Therefore, the aim of this study was to evaluate whether bovine IL-10 has immunomodulatory activities on human monocytes and dendritic cells. Peripheral blood monocytes were isolated from healthy donors, and used directly or allowed to differentiate to dendritic cells under the influence of IL-4 and GM-CSF. Recombinant bovine IL-10 inhibited TLR induced activation of monocytes, and dose-dependently inhibited LPS-induced activation of monocyte-derived DCs comparable to human IL-10. By using blocking antibodies to either bovine IL-10 or the human IL-10 receptor it was demonstrated that inhibition of monocyte activation by bovine IL-10 was dependent on binding of bovine IL-10 to the human IL-10R. These data demonstrate that bovine IL-10 potently inhibits the activation of human myeloid cells in response to TLR activation. Bovine IL-10 present in dairy products may thus potentially contribute to the prevention of necrotizing enterocolitis and allergy, enhance mucosal tolerance induction and decrease intestinal inflammation and may therefore be applicable in infant foods and in immunomodulatory diets.

Bystander suppression to unrelated allergen sensitization through intranasal administration of tolerogenic exosomes in mouse

Exosomes represent a new family of bioactive nanovesicles (30–100 nm in diameter) secreted by different cell types whose appealing features can be exploited for designing vaccines in the context of several human diseases. We previously reported the potential of bronchoalveolar lavage fluid (BALF)-derived tolerogenic exosomes (Exo Tol) to be used as a nasal allergy vaccine in a mouse model of sensitization to Ole e 1, the main allergen of olive pollen. The aim of the study was to investigate whether such nanovesicles specific to Ole e 1 can also prevent the sensitization to other unrelated allergen, as Bet v 1 from birch pollen. Exo Tol were isolated from BALF of mice tolerized against Ole e 1 and used in a prophylactic approach. BALB/c mice were intranasally pretreated with Exo Tol one week before sensitization/challenge with Bet v 1, and the magnitude of allergen-specific response was analyzed. Intranasal pretreatment with Exo Tol resulted in significant inhibition of both specific IgE and IgG1 antibodies levels. Moreover, T cells from mice pretreated with Exo Tol showed a reduction in IL-5 and IL-13 (Th2 cytokines) production. Lung inflammatory response triggered by unrelated allergen-challenge was also significantly reduced after pretreatment: perivascular/peribronchial inflammatory cell infiltration, eosinophilia and mucus secretion. In conclusion, Exo Tol specific to Ole e 1, in addition to inhibit specific immune response to this allergen, blocked the allergic response to a second unrelated allergen such as Bet v 1. The in vivo “bystander suppression” that we herein describe for Exo Tol may have implications for the treatment of allergy based on mucosal tolerance induction.

Long term immunologic consequences of experimental stroke and mucosal tolerance

BackgroundAn inflammatory insult following middle cerebral artery occlusion (MCAO) is associated with a predisposition to develop a deleterious autoimmune response to the brain antigen myelin basic protein (MBP). Induction of immunologic tolerance to brain antigens prior to MCAO prevents this deleterious autoimmune response and is associated with better functional outcome early after stroke. In this study, we sought to determine the long term immunologic consequences of experimental stroke and induction of mucosal tolerance.MethodsMale Lewis rats were tolerized to MBP or ovalbumin (OVA) by intranasal administration prior to MCAO and administration of lipopolysaccharide (LPS). Neurological outcome was assessed at set points after MCAO and animals sacrificed at 3 months; the immune response to MBP in brain and spleen was determined using ELISPOT assay and degree of cellular inflammatory brain infiltrate assessed by immunocytochemistry.ResultsAnimals that developed a pro-inflammatory (TH1) response to MBP experienced worse outcome, while those that developed a regulatory response (TREG) experienced better outcome. A TREG response in spleen was also associated with decreased inflammation and an increase in the number of FoxP3 positive cells in brain. In this study, tolerization to MBP prior to MCAO was associated with a tendency to develop a TH1 response to MBP by 3 months after MCAO.ConclusionThese data show that induction of immunological tolerance to MBP is associated with improved outcome after stroke. This study, however, raises concern about the potential for inadvertent induction of detrimental autoimmunity through mucosal administration of antigen.

Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial

BackgroundAutoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human cartilage glycoprotein-39 (HC gp-39)...

Different mechanisms regulate CD4+ T cell independent induction of oral and nasal tolerance of CD8+ T cells

Mucosal administration of antigens is known to induce antigen specific regulatory CD4(+) T cells, but less is known about the effects on CD8(+) T cell function. Using a murine model for mucosal tolerance induction, we show that both oral and nasal OVA (ovalbumin) application reduced OVA specific CD8(+) T effector cell numbers and suppressed in vivo cytotoxicity in response to subsequent immunisation. To investigate whether CD4(+) T cells are essential for oral or nasal CD8(+) T cell tolerance, we used MHC class II deficient mice. Normal CD8(+) T cell tolerance was observed in MHC class II deficient mice, indicating that CD4(+) T cells are not required for both oral and nasal CD8(+) T cell tolerance induction. To study the direct effects of mucosal antigen application on naive CD8(+) T cells, we adoptively transferred OVA specific transgenic CD8(+) T cells and analysed their fate after mucosal antigen application. Oral OVA application reduced the numbers of OVA specific CD8(+) T cells, whereas nasal OVA application induced proliferation. However, the expanded population of OVA specific CD8(+) T cells from nasally treated mice was unable to proliferate upon re-stimulation. In conclusion, our studies point to suppressive effects of the mucosal immune system directly on CD8(+) T cells and indicate multiple mechanisms of tolerance induction. More insight in these mechanisms of tolerance induction is necessary for the development of mucosal tolerance therapies for autoimmune diseases and allergy.

Induction of mucosal tolerance in SLE: A sniff or a sip away from ameliorating lupus?

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by aberrant immune responses against intracellularly derived self antigens. Treatment for SLE relies on the use of aggressive immunosuppressants and steroids that are nonspecific and can cause serious adverse effects. The observation that a systemic immune tolerance to self antigens or generation of regulatory T cells may follow mucosal (nasal or oral) exposure to self proteins or monoclonal antibody against CD3 respectively suggests that induction of mucosal tolerance offers the basis of a side effect-free therapy that could re-establish the ability to distinguish self from non-self and restore peripheral tolerance in individuals susceptible to developing autoimmune diseases. Here I review studies on mucosal tolerance in autoimmune diseases and discuss the therapeutic potential of inducing tolerance for the treatment of SLE.

Adaptive Foxp3 + Regulatory T Cell-Dependent and -Independent Control of Allergic Inflammation

Adaptive Foxp3(+) regulatory T (Treg) cells develop during induction of mucosal tolerance and after immunization. Large numbers of Foxp3(+) T cells have been found in inflamed tissues. We investigated the role of adaptive Foxp3(+) Treg cells in mucosal tolerance and in chronic allergic lung inflammation. We used two strains of mice that are devoid of naturally occurring Treg cells; one is capable of generating adaptive Foxp3(+) Treg cells upon exposure to antigen, whereas the other is deficient in both naturally occurring and adaptive Foxp3(+) Treg cells. We found that adaptive Foxp3(+) Treg cells were essential for establishing mucosal tolerance and for suppressing IL-4 production and lymphoid neogenesis in chronic inflammation, whereas IL-5 production and eosinophilia could be controlled by Foxp3-independent, IFN-gamma-dependent mechanisms. Thus, whereas adaptive Foxp3(+) Treg cells regulate sensitization to allergens and the severity of chronic inflammation, IFN-gamma-producing cells can play a beneficial role in inflammatory conditions involving eosinophils.

Airway inflammation induced after allergic poly‐sensitization can be prevented by mucosal but not by systemic administration of poly‐peptides

Patients with multiple sensitizations require alternative forms of treatment, as the efficacy of conventional immunotherapy is unsatisfactory. In the present study, we sought to compare the efficacy of a subcutaneously (s.c.) and a mucosally applied polyvalent vaccine to reduce allergic immune responses within airway and lung tissues. Female BALB/c mice were intraperitoneally immunized with recombinant (r)Bet v 1, rPhl p 1 and rPhl p 5, followed by an aerosol challenge of birch and phleum pollen extract. For tolerance induction, either a mixture of the immunodominant peptides or a hybrid peptide of the respective antigens was s.c. injected or intranasally applied before poly-sensitization. Mucosal but not systemic pre-treatment with poly-peptides led to significant suppression of eosinophils and IL-5 production in bronchoalveolar lavages, as well as IL-5, IL-4, IL-13 and eotaxin levels in lung cell cultures. Lung histology showed a clear reduction of cellular infiltration and mucus production only in intranasally pre-treated mice. In accordance, also the systemic immune response, characterized by IgE-dependent basophil degranulation and IL-4 levels in vitro, was significantly reduced by mucosal antigen application, but only marginally influenced by subcutaneous pre-treatment. Both treatment routes led to up-regulated CTLA4 expression in splenocytes, whereas only after mucosal pre-treatment Foxp3 expression levels were enhanced in lung CD3(+) T cells. Furthermore, intranasal but not subcutaneous application of the peptides enhanced IL-10 levels in the lungs, indicating regulatory mechanisms operating in local tolerance induction. Mucosal application of peptides is superior to systemic application in preventing both local and systemic poly-allergic T helper2 immune responses, suggesting mucosal tolerance induction as an attractive strategy for the primary and secondary prevention of allergic multi-sensitization and lung pathology.

Human colonic intra-epithelial lymphocytes are suppressor cells

Human colonic intra-epithelial lymphocytes (IEL) suppress the proliferation of autologous lamina propria lymphocytes, but not autologous peripheral blood mononuclear cells, when stimulated with phytohaemagglutinin. This suppressor function is mediated by a CD8-dependent soluble factor and is not related to the expression of the gamma delta T cell receptor. These findings may be relevant to the induction of mucosal tolerance. However, there is no defect in suppressor activity of colonic IEL in inflammatory bowel disease.

Lipopolysaccharides Modulate Allergen-Specific Immune Regulation in a Murine Model of Mucosal Tolerance Induction

Background: Farming has been widely reported to be associated with decreased risk of developing atopic disorders, but underlying immunomodulatory mechanisms are still not fully defined. We delineated T-cell functions after induction of mucosal tolerance in the context of intranasally delivered organic dust compounds, lipopolysaccharides (LPS). Methods: BALB/c mice were pretreated intranasally with ovalbumin (OVA) with or without LPS (Escherichia coli) three times (days –21, –14, –7) prior to systemic OVA sensitization (days 1 and 14) and airway allergen challenges (days 28–30). CD4+ spleen T cells from pretreated and sensitized donors were characterized for cytokine function, and transferred into naive recipients prior to subsequent OVA sensitization and challenges. Results: Intranasal OVA pretreatment suppressed Th2-mediated immune and inflammatory responses and enhanced frequency of regulatory T cells in OVA-sensitized and -challenged mice. Addition of LPS to OVA, but not LPS alone, inhibited development of allergen-induced sensitization and eosinophilic airway infiltration, and markedly enhanced allergen-specific IgG1 serum levels and frequencies of IL-10- and IFN-γ-producing CD4+ T cells. Transfer of CD4+ spleen T cells from OVA-pretreated animals protected naive recipients against subsequent allergen sensitization and airway disease, whereas transfer from LPS/OVA-pretreated animals only protected against allergen sensitization. Conclusion: Microbial LPS modulated mucosal tolerance by inducing allergen-specific IgG1 production and distinct effector CD4+ T cells with a mixed regulatory/Th1 phenotype. Organic dust components such as LPS might therefore be important immune modulators in naturally occurring or preventive allergen-specific tolerance induction.

The immune privilege of the oral mucosa

Despite high bacterial colonization and frequent allergen contact, acute inflammatory and allergic reactions are rarely seen in the oral mucosa. Therefore we assert that immune tolerance predominates at this site and antigen presenting cells, such as dendritic cells and different T cell subtypes, serve as key players in oral mucosal tolerance induction. In this article we describe the mechanisms that lead to tolerance induced in the oral mucosa and how they differ from tolerance induced in the lower gastrointestinal tract. Furthermore we discuss ways in which novel nonparenteral approaches for immune intervention, such as allergen-specific immunotherapy applied by way of the sublingual route, might be improved to target the tolerogenic properties of the sophisticated oral mucosal immune network.

Low-dose tolerance is mediated by the microfold cell ligand, reovirus protein sigma1.

Mucosal tolerance induction generally requires multiple or large Ag doses. Because microfold (M) cells have been implicated as being important for mucosal tolerance induction and because reovirus attachment protein sigma1 (psigma1) is capable of binding M cells, we postulated that targeting a model Ag to M cells via psigma1 could induce a state of unresponsiveness. Accordingly, a genetic fusion between OVA and the M cell ligand, reovirus psigma1, termed OVA-psigma1, was developed to enhance tolerogen uptake. When applied nasally, not parenterally, as little as a single dose of OVA-psigma1 failed to induce OVA-specific Abs even in the presence of adjuvant. Moreover, the mice remained unresponsive to peripheral OVA challenge, unlike mice given multiple nasal OVA doses that rendered them responsive to OVA. The observed unresponsiveness to OVA-psigma1 could be adoptively transferred using cervical lymph node CD4(+) T cells, which failed to undergo proliferative or delayed-type hypersensitivity responses in recipients. To discern the cytokines responsible as a mechanism for this unresponsiveness, restimulation assays revealed increased production of regulatory cytokines, IL-4, IL-10, and TGF-beta1, with greatly reduced IL-17 and IFN-gamma. The induced IL-10 was derived predominantly from FoxP3(+)CD25(+)CD4(+) T cells. No FoxP3(+)CD25(+)CD4(+) T cells were induced in OVA-psigma1-dosed IL-10-deficient (IL-10(-/-)) mice, and despite showing increased TGF-beta1 synthesis, these mice were responsive to OVA. These data demonstrate the feasibility of using psigma1 as a mucosal delivery platform specifically for low-dose tolerance induction.

Transfer of T cells from intranasal ovalbumin-immunized mice ameliorates allergic response in ova-sensitized recipient mice

Mucosal immunotherapy is suggested as a treatment strategy for tolerance induction in allergic diseases. The purpose of this study was to determine the effect of transferred splenic T cells from intranasal ovalbumin (OVA)-immunized mice to naive mice before sensitization on its impact of cytokine production and airway histopathology. BALB/c mice in group I received intranasal immunotherapy (days1-6), carboxylfluorescein succinyl ester (CFSE)-labeled splenocytes or splenic T cells were i.v. transferred to naive recipients (group II) before OVA sensitization. Acute murine asthma model was established by two i.p. OVA injections (days 21 and 28) and seven OVA nebulizations (days 42-48) in groups I, II and III. Groups III and IV served as asthma model and control, respectively. CFSE-labeled cells in splenocytes and lymph node lymphocytes, lung histopathology, IL-4, IL-10, and interferon (IFN) gamma cytokines of recipients were analyzed 24 hours after OVA nebulization challenge. CFSE-labeled T cells from group I were detected in spleen and regional lymph nodes of the OVA-sensitized recipients (group II). Smooth muscle and thickness of airways were less in intranasal OVA immunotherapy and OVA-sensitized recipients when compared with the asthma model (p < 0.05). Area of inflammation was significantly suppressed in OVA-sensitized recipients compared with the asthma model (p < 0.01). IL-10 and IFN-gamma levels in splenocyte supernatants were significantly increased in intranasal immunotherapy and OVA-sensitized recipients compared with asthma model and controls (p < 0.01). IL-4 levels were significantly less in intranasal immunotherapy group and the OVA-sensitized recipient group when compared with asthma the model group (p < 0.05). This study suggests that intranasal immunotherapy with allergens regulates T-cell responses and ameliorates airway histopathology in sensitized mice, hence, encouraging mucosal tolerance induction as a suitable treatment of allergic diseases.

Innate and adaptive mechanisms to control of pathological intestinal inflammation

The intestine is the home of a tremendous number of commensal organisms that have a primary role in host metabolism. As a consequence, the gut mucosa has evolved multiple layers of protection. This review highlights both innate and adaptive mechanisms that prevent bacterial invasion and abnormal intestinal inflamamation, how a failure of these mechanisms may be involved in the pathogenesis of inflammatory bowel diseases, and discusses new findings implicating dendritic cells as central to the induction of active mucosal tolerance to commensal bacteria.

Fetomaternal Alloimmunization with Antenatal Glomerulopathies

Fetomaternal alloimmunization with antenatal glomerulopathies (FMAIG) is a recently described alloimmune disorder, which results from maternal antibodies that cross the placenta, bind to fetal glomerular podocytes, and mediate renal disease. The pathogenic antibodies are directed against neutral endopeptidase (NEP). The infant's mother is NEP-deficient and thus she becomes immunized during pregnancy against NEP expressed by placental cells. Because future pregnancies in NEP-immunized mothers are at high risk for the fetus, detection of anti-NEP antibodies in pregnant mothers and antigen-driven therapies including induction of mucosal tolerance, are urgently needed. This ideally requires identification of the pathogenic epitopes born by the antigen. We have recently characterized two linear B cell epitopes on the NEP that are specifically recognized by the mother's antibodies. The identification of these B cell epitopes is useful for diagnostic tests and may lead to future development of new therapeutic approaches based on peptide-specific immune intervention.

Intranasal immunization with a dominant T-cell epitope peptide of a major allergen of olive pollen prevents mice from sensitization to the whole allergen

Mucosal tolerance induction with vaccines based on peptides representing T-cell epitopes of allergens is a promising way for treating allergic diseases. Ole e 1 is the main allergen of olive pollen, which is an important cause of allergy in Mediterranean countries. The aim of this study was to evaluate the ability of the peptide T109-K130 containing a dominant T-cell epitope of Ole e 1, to modulate the allergen-specific immune response in a prophylactic mouse model. Mice were intranasally treated with the peptide 1 week prior to sensitization with Ole e 1. Blood, lungs and spleens were collected and analysed for immune response. Intranasal pretreatment of mice with the peptide led to suppress serum specific IgE, IgG1 and IgG2a antibody levels, and markedly reduced proliferative T-cell response and Th2-cytokine production, but increased IFN-γ secretion in spleen cell cultures. Increased mRNA IL-10 levels were observed in lungs from pretreated mice. Pathologic alterations of the lung associated with airway inflammation (peribronchial/perivascular infiltrates, eosinophilia and mucus production) were significantly suppressed after pretreatment. Similar results were obtained when mice were sensitized 10 weeks after treatment. Our results demonstrate that intranasal administration of a single T-cell peptide protects mice against subsequent sensitization to the allergen, possibly via IFN-γ and IL-10. This study emphasizes the usefulness of nasal peptide T-based vaccines against allergy.

The impact of cell-bound antigen transport on mucosal tolerance induction

Mucosal surfaces are exposed continuously to a flood of foreign antigens demanding a tightly controlled balance between immunity and tolerance induction. Tolerance toward food and inhaled antigens, known as oral and respiratory tolerance, respectively, evokes a body-wide nonresponsiveness against the plethora of environmental antigens. Key issues in understanding the induction of mucosal tolerance relate to the site of antigen entrance, the mechanisms of antigen transport, and the exact anatomical location where lymphocytes meet their cognate antigens. In this regard, opposing ideas have been put forward: In one scenario, antigens taken up at mucosal surfaces are considered to spread throughout the body, thus potentially evoking tolerogenic immune responses in all secondary lymphoid organs. Alternatively, tolerance induction might be confined to the draining regional lymph nodes (LN). Recent observations strongly supported the latter scenario, emphasizing the importance of regional LN and their network of afferent lymphatics in this process. In this model, air-borne and intestinal antigens are captured at mucosal sites by dendritic cells, which then migrate exclusively in a CCR7-dependent way to draining regional LN. Tolerance is then induced actively by the activation of antigen-specific T cells, which are subsequently deleted, become anergic, or alternatively, differentiate into regulatory T cells. Thus, the concept of local induction of immune responses seems to hold true for the majority of immune reactions, regardless of whether they are tolerogenic or defensive in their outcome.

Improvement of sublingual immunotherapy efficacy with a mucoadhesive allergen formulation

Sublingual immunotherapy is a noninvasive and efficacious treatment of type I respiratory allergies. A murine model of sublingual immunotherapy is needed to understand better the immune mechanisms involved in successful immunotherapy and to assess second-generation candidate vaccines. Herein, we developed a therapeutic murine model of sublingual immunotherapy in which we document the value of mucoadhesive formulations to enhance treatment efficacy. BALB/c mice were sublingually treated with soluble or formulated ovalbumin before or after sensitization with ovalbumin. Airways hyperresponsiveness and lung inflammation were assessed by whole-body plethysmography and lung histology, respectively. Humoral and cellular immune responses were monitored by ELISA and ELISPOT techniques. Prophylactic sublingual administration of ovalbumin completely prevents airways hyperresponsiveness as well as IL-5 secretion and IgE induction. Therapeutic administration of ovalbumin as a solution via either the sublingual or oral route has a limited efficacy. In contrast, sublingual application of ovalbumin formulated with maltodextrin to enhance mucosal adhesion results in a major reduction of established airways hyperresponsiveness, lung inflammation, and IL-5 production in splenocytes. This mucoadhesive formulation significantly enhances ovalbumin-specific T-cell proliferation in cervical but not mesenteric lymph nodes, and IgA production in the lungs. A mucoadhesive maltodextrin formulation of ovalbumin enhances priming of the local mucosal immune system and tolerance induction via the sublingual route. Mucoadhesive formulations offer the opportunity to improve dramatically sublingual immunotherapy in human beings, most particularly by simplifying immunization schemes.