State of the Art on Food Allergy Immunotherapy

Food allergy is increasing in prevalence in westernized countries, leading to significant morbidity including nutritional deficiencies and the potential for fatal anaphylaxis during accidental exposure to the allergen. The current treatment remains strict avoidance, although the disease is not cured. Allergen specific immunotherapy for food allergy is currently being actively evaluated, but is still experimental. Nevertheless, it is the only disease-modifying therapy for IgE-mediated food allergy and appears to be a promising method of desensitization and tolerance achievement. Despite the success of different protocols studied in clinical trials (oral, sublingual and epicutaneous immunotherapy), the main drawback is the appearance of adverse reactions, which impacts in the patient adherence to the treatment. The mechanisms underlying successful food desensitization are also unclear, in part because there is no standard immunotherapy protocol and different mechanisms have been proposed. The treatment variations currently being investigated increases the likelihood of finding novel or modified therapies for food allergy. In this regard, mouse models of experimental allergy constitute a valuable biological tool to elucidate and understand these mechanisms, and to evaluate novel therapeutic strategies.Facultad de Ciencias ExactasInstituto de Estudios Inmunológicos y Fisiopatológico

New Insights in Immunotherapies for Food Allergies : A Path between the Mouse Model and the Allergic Patient

Allergic diseases are the most prevalent immunopathologies worldwide. Nowadays, allergen avoidance is the unique effective treatment for allergic patients. Pre-clinical studies and clinical trials have been successful to prove that immunotherapies may accomplish mucosal mechanisms of allergen-specific tolerance, which are able to revoke the allergic sensitization. Although more than 100 years have elapsed since the first reported procedure achieved in patients sensitive to pollen, the main obstacle in these therapies still remains adverse reactions induced during treatment. The need for further studies is required to explore safe and effective therapeutic protocols. More recently, immunotherapy appears to be an attractive option for patients with food allergy, although it is still experimental. Different strategies were proposed to overcome the concerning adverse effects that compromise safety, effectiveness and compliance with treatments. At this point, translational medicine is a flourish field in the arenas of basic science, applied science, and clinical research. The use of experimental animals may provide new insights to unravel mechanisms that play key roles in desensitization and tolerance induction, and to modify existing protocols or design new therapeutic approaches. The present reviews describes the different immunotherapies that are used in allergic patients, the promising immune interventions that are currently evaluated in clinical trials and the contributions that animal models may provide to improve the quality of treatments.Facultad de Ciencias ExactasInstituto de Estudios Inmunológicos y Fisiopatológico

New Insights in Immunotherapies for Food Allergies : A Path between the Mouse Model and the Allergic Patient

Allergic diseases are the most prevalent immunopathologies worldwide. Nowadays, allergen avoidance is the unique effective treatment for allergic patients. Pre-clinical studies and clinical trials have been successful to prove that immunotherapies may accomplish mucosal mechanisms of allergen-specific tolerance, which are able to revoke the allergic sensitization. Although more than 100 years have elapsed since the first reported procedure achieved in patients sensitive to pollen, the main obstacle in these therapies still remains adverse reactions induced during treatment. The need for further studies is required to explore safe and effective therapeutic protocols. More recently, immunotherapy appears to be an attractive option for patients with food allergy, although it is still experimental. Different strategies were proposed to overcome the concerning adverse effects that compromise safety, effectiveness and compliance with treatments. At this point, translational medicine is a flourish field in the arenas of basic science, applied science, and clinical research. The use of experimental animals may provide new insights to unravel mechanisms that play key roles in desensitization and tolerance induction, and to modify existing protocols or design new therapeutic approaches. The present reviews describes the different immunotherapies that are used in allergic patients, the promising immune interventions that are currently evaluated in clinical trials and the contributions that animal models may provide to improve the quality of treatments.Facultad de Ciencias ExactasInstituto de Estudios Inmunológicos y Fisiopatológico

New Insights in Immunotherapies for Food Allergies : A Path between the Mouse Model and the Allergic Patient

Allergic diseases are the most prevalent immunopathologies worldwide. Nowadays, allergen avoidance is the unique effective treatment for allergic patients. Pre-clinical studies and clinical trials have been successful to prove that immunotherapies may accomplish mucosal mechanisms of allergen-specific tolerance, which are able to revoke the allergic sensitization. Although more than 100 years have elapsed since the first reported procedure achieved in patients sensitive to pollen, the main obstacle in these therapies still remains adverse reactions induced during treatment. The need for further studies is required to explore safe and effective therapeutic protocols. More recently, immunotherapy appears to be an attractive option for patients with food allergy, although it is still experimental. Different strategies were proposed to overcome the concerning adverse effects that compromise safety, effectiveness and compliance with treatments. At this point, translational medicine is a flourish field in the arenas of basic science, applied science, and clinical research. The use of experimental animals may provide new insights to unravel mechanisms that play key roles in desensitization and tolerance induction, and to modify existing protocols or design new therapeutic approaches. The present reviews describes the different immunotherapies that are used in allergic patients, the promising immune interventions that are currently evaluated in clinical trials and the contributions that animal models may provide to improve the quality of treatments.Facultad de Ciencias ExactasInstituto de Estudios Inmunológicos y Fisiopatológico

The Major Soybean Allergen Gly m Bd 28K Induces Hypersensitivity Reactions in Mice Sensitized to Cow's Milk Proteins

Reactions to soy have been reported in a proportion of patients with IgE-mediated cow’s milk allergy (CMA). In this work, we analyzed if Gly m Bd 28K/P28, one of the major soybean allergens, is a cross-reactive allergen with cow milk proteins (CMP). We showed that P28 was recognized by IgE sera from CMA patients and activated human peripheral basophils degranulation. Moreover, IgE sera of mice exclusively sensitized to CMP recognized P28. Splenocytes from sensitized animals secreted IL-5 and IL-13 when incubated with CMP or soy proteins, but only IL-13 when treated with P28. In addition, a skin test was strongly positive for CMP and weakly positive for P28. Remarkably, milk-sensitized mice showed hypersensitivity symptoms following sublingual challenge with P28 or CMP. With the use of bioinformatics’ tools seven putative cross-reactive epitopes were identified. In conclusion, using in vitro and in vivo tests we demonstrated that P28 is a novel cross-reactive allergen with CMP.Fil: Candreva, Ángela María. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Smaldini, Paola Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Curciarello, Renata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Fossati, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Docena, Guillermo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Petruccelli, Silvana. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; Argentin

Oral delivery of Brucella spp. recombinant protein U-Omp16 abrogates the IgE-mediated milk allergy

Food allergies are increasingly common disorders and no therapeutic strategies are yet approved. The unlipidated Omp16 (U-Omp16) is the outer membrane protein of 16 kDa from B. abortus and possesses a mucosal adjuvant property. In this study, we aimed to examine the U-Omp16 capacity to abrogate an allergen-specific Th2 immune response when it is administered as an oral adjuvant in a mouse model of food allergy. Balb/c mice were sensitized with cholera toxin and cow's milk proteins (CMP) by gavage and simultaneously treated with U-Omp16 and CMP. Oral challenge with CMP was performed to evaluate the allergic status of mice. Symptoms, local (small bowel cytokine and transcription factor gene expression) and systemic (specific isotypes and spleen cell-secreted cytokines) parameters, and skin tests were done to evaluate the immune response. We found that the oral administration of U-Omp16 with CMP during sensitization dampened the allergic symptoms, with negativization of immediate skin test and increased skin DTH response. Serum specific IgE and IL-5 were inhibited and a Th1 response was promoted (specific IgG2a antibodies and CMP-induced IFN-γ secretion). We found at the mucosal site an inhibition of the gene expression corresponding to IL-13 and Gata-3, with an induction of IFN-γ and T-bet. These results indicated that the oral administration of U-Omp16 significantly controlled the allergic response in sensitized mice with a shift of the balance of Th1- and Th2-T cells toward Th1 predominance. These findings suggest that U-Omp16 may be useful as a Th1-directing adjuvant in an oral vaccine.Laboratorio de Investigaciones del Sistema Inmun

Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells

Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long‐term tolerance. In this work, we combined SLIT with systemic administration of IL‐2 associated with an anti‐IL‐2 monoclonal antibody (IL‐2/anti‐IL‐2Ab complex or IL‐2C) to reverse the IgE‐mediated experimental allergy. Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL‐2C. The animals were next re‐exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. The treatment reduced serum specific IgE, IL‐5 secretion by spleen cells and increased IL‐10 and TGF‐β in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL‐10‐secreting CD4+CD25+Foxp3+ regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. The combination of two therapeutic strategies rendered Treg‐mediated tolerance more efficient compared to individual treatments and reversed the established IgE‐mediated food allergy. This approach highlights the ability of IL‐2C to expand Tregs, and it may represent a promising disease‐modifying therapy for managing food allergyInstituto de Estudios Inmunológicos y FisiopatológicosConsejo Nacional de Investigaciones Científicas y Técnica

Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells

Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long‐term tolerance. In this work, we combined SLIT with systemic administration of IL‐2 associated with an anti‐IL‐2 monoclonal antibody (IL‐2/anti‐IL‐2Ab complex or IL‐2C) to reverse the IgE‐mediated experimental allergy. Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL‐2C. The animals were next re‐exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. The treatment reduced serum specific IgE, IL‐5 secretion by spleen cells and increased IL‐10 and TGF‐β in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL‐10‐secreting CD4+CD25+Foxp3+ regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. The combination of two therapeutic strategies rendered Treg‐mediated tolerance more efficient compared to individual treatments and reversed the established IgE‐mediated food allergy. This approach highlights the ability of IL‐2C to expand Tregs, and it may represent a promising disease‐modifying therapy for managing food allergyInstituto de Estudios Inmunológicos y FisiopatológicosConsejo Nacional de Investigaciones Científicas y Técnica

Peptides of amaranth were targeted as containing sequences with potential anti-inflammatory properties

The immunomodulatory effect of amaranth peptides on epithelial cells activated through the NF-κB signalling pathway was examined. Results showed that extensive protein hydrolysis from amaranth (23 and 30% degree of hydrolysis) reduced the emission of light in bacterial flagellin-activated Caco-2 CCL20: luc cells (Caco-2 cells transfected with a luciferase reporter under the control of the CCL20 promoter) compared with the non-hydrolysed protein. Purification of the most active peptide fractions by HPLC chromatography and sequencing showed that the peptide SSEDIKE possessed a modulatory capacity on activated cells to suppress the expression of mRNA coding for CCL20. This peptide was non-toxic for cells. These findings indicated that the peptide SSEDIKE derived from proteins of amaranth attenuated the activation of human intestinal epithelial cell, and hence amaranth proteins could be included in functional foods as a source of bioactive peptides with health promoting properties.Centro de Investigación y Desarrollo en Criotecnología de Alimento

The Major Soybean Allergen Gly m Bd 28K Induces Hypersensitivity Reactions in Mice Sensitized to Cow's Milk Proteins

Reactions to soy have been reported in a proportion of patients with IgE-mediated cow’s milk allergy (CMA). In this work, we analyzed if Gly m Bd 28K/P28, one of the major soybean allergens, is a cross-reactive allergen with cow milk proteins (CMP). We showed that P28 was recognized by IgE sera from CMA patients and activated human peripheral basophils degranulation. Moreover, IgE sera of mice exclusively sensitized to CMP recognized P28. Splenocytes from sensitized animals secreted IL-5 and IL-13 when incubated with CMP or soy proteins, but only IL-13 when treated with P28. In addition, a skin test was strongly positive for CMP and weakly positive for P28. Remarkably, milk-sensitized mice showed hypersensitivity symptoms following sublingual challenge with P28 or CMP. With the use of bioinformatics’ tools seven putative cross-reactive epitopes were identified. In conclusion, using in vitro and in vivo tests we demonstrated that P28 is a novel cross-reactive allergen with CMP.Centro de Investigación y Desarrollo en Criotecnología de AlimentosInstituto de Estudios Inmunológicos y Fisiopatológico