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Howard L. Weiner - One of the best experts on this subject based on the ideXlab platform.
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Cellular Components and Mechanisms of Oral Tolerance Induction.
Critical reviews in immunology, 2018Co-Authors: Rafael Machado Rezende, Howard L. WeinerAbstract:Oral Tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the Oral route. Multiple mechanisms of Tolerance are induced by Oral-fed antigens, but induction of regulatory CD4 T-cells expressing the transcription factor Foxp3 and the membrane-bound TGF-β stands out as the major players in Oral Tolerance. Oral antigen administration suppresses several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes, but also nonautoimmune inflammatory conditions such as asthma, atherosclerosis, graft rejection, allergy, and stroke. However, human trials have produced mixed results, and a great deal remains to be learned about the mechanisms of Oral Tolerance before it can be successfully applied to people. In this review, we highlight the cellular components involved in Oral Tolerance induction. A deep knowledge of these intricate cell interactions will pave the way for a successful application of antigen Tolerance to treat autoimmune and nonautoimmune inflammatory diseases.
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History and mechanisms of Oral Tolerance.
Seminars in immunology, 2017Co-Authors: Rafael Machado Rezende, Howard L. WeinerAbstract:Since its first description by Wells and Osbourne in 1911, Oral Tolerance has intrigued researchers due to its potential for therapeutic applications. Oral Tolerance can be defined as an inhibition of specific immune responsiveness to subsequent parenteral injections of proteins to which an individual or animal has been previously exposed via the Oral route. Tolerance induction to commensal bacteria and dietary proteins represents the major immunological event taking place in the gut in physiological conditions. Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens: low doses of Orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. In this review, we highlight historical aspects and the mechanisms proposed for Oral Tolerance induction.
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Mechanisms of Oral Tolerance to Soluble Protein Antigens
Mucosal Immunology, 2015Co-Authors: Oliver Pabst, Andre Pires Da Cunha, Howard L. WeinerAbstract:Abstract 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. Although most immune cells present in the gut display an activated state, in physiological conditions Tolerance induction is the default immune pathway at this site. Immunological Tolerance to antigens that gain access to the body via the Oral route has been termed “Oral Tolerance” and appears to be physiologically important to prevent intestinal disorders, such as food allergy, celiac disease, and inflammatory bowel disease. Because of its unique immunological properties, Oral Tolerance is an attractive approach for the development of nontoxic and more effective treatments for different inflammatory and autoimmune diseases. Here we review the basic mechanisms underlying the establishment and maintenance of Oral Tolerance and discuss the potential to translate it more effectively to the clinic.
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Oral Tolerance and TGF-beta-producing cells.
Inflammation & allergy drug targets, 2006Co-Authors: Ana Maria Caetano Faria, Howard L. WeinerAbstract:Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens, a phenomenon named Oral Tolerance. Low doses of Orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. A major conceptual advance in Oral Tolerance has been the demonstration that TGF-beta plays a central role in Oral Tolerance as a mediator secreted by Th3 cells. In addition, recent pieces of evidence suggest that TGF-beta may be a primary link between distinct populations of regulatory T cells that are induced by feeding. Conversion of CD4+CD25- into CD4+CD25+ T cells by the expression of FoxP3 involves TGF-beta. A membrane-bound form of TGF-beta (containing latency-associated peptide - LAP) has also been described and LAP+ CD4+ T cells mediate suppression in the gut by a TGF-beta-dependent mechanism. Most of these regulatory T cells are anergic cells indicating that anergy may be also related to Treg induction. Moreover, deletional events taking place in the gut mucosa induce TGF-beta production by either macrophages that phagocyte apoptotic cells or by the dying T cells. Thus, it appears that TGF-beta-producing cells are not only crucial for Oral Tolerance, but they may be master regulators of most of the mechanisms triggered by antigen feeding.
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Oral Tolerance: therapeutic implications for autoimmune diseases.
Clinical & developmental immunology, 2006Co-Authors: Ana Maria Caetano Faria, Howard L. WeinerAbstract:Oral Tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the Oral route. Multiple mechanisms of Tolerance are induced by Oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of Oral Tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to Oral Tolerance, nasal Tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal Tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral Tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal Tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of Oral Tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus Oral), formulation, mucosal adjuvants, combination therapy and early therapy.
Lloyd Mayer - One of the best experts on this subject based on the ideXlab platform.
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Oral Tolerance and inflammatory bowel disease.
Current opinion in gastroenterology, 2005Co-Authors: Thomas Kraus, Lloyd MayerAbstract:Oral Tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used Oral Tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of Oral Tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use Oral Tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for Oral Tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding Oral Tolerance, explore the relation between Oral Tolerance and inflammatory bowel disease, and comment on the likelihood of successful Oral Tolerance therapy for inflammatory bowel disease. The results of an Oral Tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced Oral Tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce Oral Tolerance is not successful in patients with inflammatory bowel disease. The fundamental difference in the mechanisms of Oral Tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before Oral Tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.
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Oral Tolerance and inflammatory bowel disease.
Current opinion in gastroenterology, 2005Co-Authors: Thomas Kraus, Lloyd MayerAbstract:Purpose of review Oral Tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used Oral Tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of Oral Tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use Oral Tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for Oral Tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding Oral Tolerance, explore the relation between Oral Tolerance and inflammatory bowel disease, and comment on the likelihood of successful Oral Tolerance therapy for inflammatory bowel disease. Recent findings The results of an Oral Tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced Oral Tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce Oral Tolerance is not successful in patients with inflammatory bowel disease. Summary The fundamental difference in the mechanisms of Oral Tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before Oral Tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.
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Oral Tolerance: lessons on treatment of food allergy.
European journal of gastroenterology & hepatology, 2005Co-Authors: Lloyd MayerAbstract:Oral Tolerance is the active non-response by the immune system to an antigen administered through the Oral route. It is postulated that food hypersensitivity results from a breakdown in Oral Tolerance induction, and the importance of Oral Tolerance in food hypersensitivity can be traced back to classic experiments from 1911 in which guinea pigs were protected from anaphylaxis by prior feeding of antigen. Host and antigenic factors play a role in determining the pathways and mechanisms to which a fed antigen can gain Tolerance. Recent studies have demonstrated the potential of using Oral Tolerance to treat food allergies, and additional studies are necessary to further our understanding of mechanisms of Oral Tolerance induction.
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Oral Tolerance and its relation to food hypersensitivities.
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Mirna Chehade, Lloyd MayerAbstract:The gastrointestinal tract is the largest immunologic organ in the body. It is constantly bombarded by a myriad of dietary proteins. Despite the extent of protein exposure, very few patients have food allergies because of development of Oral Tolerance to these antigens. Once proteins contact the intestinal surface, they are sampled by different cells and, depending on their characteristics, result in different responses. Antigens might be taken up by Microfold cells overlying Peyer's patches, dendritic cells, or epithelial cells. Different cells of the immune system participate in Oral Tolerance induction, with regulatory T cells being the most important. Several factors can influence Tolerance induction. Some are antigen related, and others are inherent to the host. Disturbances at different steps in the path to Oral Tolerance have been described in food hypersensitivity. In this review we provide an overview of Oral Tolerance and cite data related to food hypersensitivity wherever evidence is available.
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Treatment of disease through Oral Tolerance.
Discovery medicine, 2004Co-Authors: Ling Shao, Lloyd MayerAbstract:Extract: The immune response to soluble protein antigens differs markedly depending on the route by which that antigen enters the body. In particular, early studies demonstrated that antigens that were first encountered via the gastrointestinal tract (e.g., via Oral administration) led to systemic hyporesponsiveness against that antigen. This phenomenon has been termed Oral Tolerance. Further studies in mouse models of human disease demonstrated the potential for Oral Tolerance to protect susceptible animals from developing inflammatory and/or autoimmune diseases. This breakthrough finding lead to a surge in interest in Oral Tolerance as a potential prophylactic/therapeutic agent in human diseases. Here we briefly describe the underlying mechanisms and important factors influencing Oral Tolerance elucidated through animal models and conclude with a discussion on the translation of these findings to human beings. Numerous studies in mice have demonstrated that the dose of antigen administered is a critical factor influencing Oral Tolerance. Moreover, two forms of Oral Tolerance have been delineated which differ in their mechanism of action. High doses of antigen lead to the deletion of antigen-reactive T lymphocytes (T-cells).
Ana Maria Caetano Faria - One of the best experts on this subject based on the ideXlab platform.
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Oral Tolerance and TGF-beta-producing cells.
Inflammation & allergy drug targets, 2006Co-Authors: Ana Maria Caetano Faria, Howard L. WeinerAbstract:Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens, a phenomenon named Oral Tolerance. Low doses of Orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. A major conceptual advance in Oral Tolerance has been the demonstration that TGF-beta plays a central role in Oral Tolerance as a mediator secreted by Th3 cells. In addition, recent pieces of evidence suggest that TGF-beta may be a primary link between distinct populations of regulatory T cells that are induced by feeding. Conversion of CD4+CD25- into CD4+CD25+ T cells by the expression of FoxP3 involves TGF-beta. A membrane-bound form of TGF-beta (containing latency-associated peptide - LAP) has also been described and LAP+ CD4+ T cells mediate suppression in the gut by a TGF-beta-dependent mechanism. Most of these regulatory T cells are anergic cells indicating that anergy may be also related to Treg induction. Moreover, deletional events taking place in the gut mucosa induce TGF-beta production by either macrophages that phagocyte apoptotic cells or by the dying T cells. Thus, it appears that TGF-beta-producing cells are not only crucial for Oral Tolerance, but they may be master regulators of most of the mechanisms triggered by antigen feeding.
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Oral Tolerance: therapeutic implications for autoimmune diseases.
Clinical & developmental immunology, 2006Co-Authors: Ana Maria Caetano Faria, Howard L. WeinerAbstract:Oral Tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the Oral route. Multiple mechanisms of Tolerance are induced by Oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-b) regulatory T cells (Tregs) plus CD4þCD25þ regulatory cells and LAPþT cells. Induction of Oral Tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-b, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to Oral Tolerance, nasal Tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal Tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral Tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal Tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of Oral Tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus Oral), formulation, mucosal adjuvants, combination therapy and early therapy.
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Alcohol-induced gastritis prevents Oral Tolerance induction in mice
Clinical and experimental immunology, 2006Co-Authors: Mariléia Chaves Andrade, J. S. Menezes, G.d. Cassali, Olindo Assis Martins-filho, Denise Carmona Cara, Ana Maria Caetano FariaAbstract:Despite several reports on the immunological relationship between inflammatory bowel diseases and immunoregulatory mechanisms in the gut, systematic studies addressing the impact of inflammatory processes in the gastric mucosa on events, such as Oral Tolerance, are still limited. Herein, we report the establishment of a novel murine model of gastritis induced by short-term administration of ethanol. The major immumological features of this clinical entity are characterized, as well as its impact on the induction of Oral Tolerance. Our data demonstrate that ethanol ingestion during 4 consecutive days triggered an acute inflammatory reaction in the stomach referred as ethanol-induced gastritis and characterized by hyperaemia, oedema and mixed mononuclear/polymorphonuclear cell infiltrate. Besides local immunological changes, such as high levels of gastric interleukin (IL)-4 and interferon (IFN)-γ, systemic alterations are also observed, including increased IL-4 synthesis, enhanced levels of serum IgE and absence of IL-10 production by spleen cells. Moreover, ethanol-induced gastritis prevents Oral Tolerance induction to ovalbumin (OVA) as demonstrated by unaltered anti-OVA humOral and cellular immune responses in treated animals. Tissue eosinophilia after footpad immunization with OVA suggests that Oral treatment with ethanol induced an allergic-type reaction. Taken together, our findings indicate that short-term ethanol ingestion is associated with gastric inflammatory events able to break immunoregulatory mechanisms that maintain mucosal homeostasis and Oral Tolerance.
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Genetic Selection for Resistance or Susceptibility to Oral Tolerance to Ovalbumin Affects General Mechanisms of Tolerance Induction in Mice
Annals of the New York Academy of Sciences, 2004Co-Authors: Alice O Kamphorst, Antonio Carlos Da Silva, Cláudia R. Carvalho, M F Silva, Ana Maria Caetano FariaAbstract:: To study the genes involved in Oral Tolerance susceptibility, two strains of mice were genetically selected for susceptibility (TS) and resistance (TR) to Oral Tolerance to ovalbumin by bidirectional breeding. Herein we show that the genetic selection process is restricted neither to ovalbumin nor to Oral Tolerance. It affected Oral Tolerance to other proteins, such as casein, and Tolerance induced the intravenous route.
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Induction of Oral Tolerance to cellular immune responses in the absence of Peyer's patches.
European journal of immunology, 2001Co-Authors: Thomas W. Spahn, Ana Maria Caetano Faria, Adriano Fontana, Anthony J. Slavin, Hans-pietro Eugster, Xingmin Zhang, Pandelakis A. Koni, Nancy H. Ruddle, Richard A. Flavell, Paul D. RennertAbstract:Systemic hyporesponsiveness occurs following Oral administration of antigen (Oral Tolerance) and involves the uptake and processing of antigen by the gut-associated lymphoid tissue (GALT), which includes Peyer's patches (PP) lamina propria lymphocytes and mesenteric lymph nodes (MLN). Animals with targeted mutations of genes in the tumor necrosis factor (TNF) family have differential defects in the development of peripheral lymphoid organs including PP and MLN, and provide a unique opportunity to investigate the role of GALT structures in the induction of Oral Tolerance. Oral Tolerance could not be induced in TNF/lymphotoxin (LT) α–/– mice, which are devoid of both PP and MLN, although these animals could be tolerized by intraperitoneal administration of antigen, demonstrating the requirement for GALT for Oral Tolerance induction. LTβ–/– mice and LTα/LTβ+/– animals do not have PP but could be Orally tolerized, as measured by IFN-γ production and delayed-type hypersensitivity responses by administration of both low or high doses of ovalbumin. To further investigate the requirement for PP, we tested the progeny of LTβ-receptor-IgG-fusion-protein (LTβRigG)-treated mice, which do not form PP but have an otherwise intact immune system. Although these animals had decreased fecal IgA production, they could be Orally tolerized. Our results demonstrate that PP are not an absolute requirement for the induction of either high- or low-dose Oral Tolerance, although Oral Tolerance could not be induced in animals devoid of both PP and MLN.
Stephenson Strobel - One of the best experts on this subject based on the ideXlab platform.
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epicutaneous exposure to peanut protein prevents Oral Tolerance and enhances allergic sensitization
Clinical & Experimental Allergy, 2005Co-Authors: Jessica Strid, Jonathan Hourihane, Robin Callard, Ian Kimber, Stephenson StrobelAbstract:BACKGROUND: Food allergies are an important cause of life-threatening hypersensitivity reactions. Oral Tolerance can be considered the default immune response to dietary antigens, with immune deviation resulting in allergic sensitization. However, primary sensitization to food allergens may not solely be through the gastrointestinal mucosa, as strong T-helper type 2 (Th2)-biased immunity can result from exposure to protein allergens on barrier-disrupted skin. OBJECTIVE: The purpose of this study was to examine whether exposure to allergens through the skin may interfere with the normal development of Oral Tolerance and promote allergic sensitization to food proteins. METHODS: Female BALB/c mice were exposed epicutaneously to peanut protein and induction of systemic Oral Tolerance through high dose feeds of peanut protein was subsequently assessed. Other mice were rendered tolerant prior to epicutaneous peanut exposure. Sensitivity to peanut was determined by assessing delayed-type hypersensitivity, proliferative, cytokine and antibody responses. RESULTS: Epicutaneous exposure to peanut protein induced potent Th2-type immunity with high levels of IL-4 and serum IgE. Primary skin exposure prevented the subsequent induction of Oral Tolerance to peanut in an antigen-specific manner. Upon Oral challenge, mice became further sensitized and developed strong peanut-specific IL-4 and IgE responses. Furthermore, animals with existing Tolerance to peanut were partly sensitized following epicutaneous exposure. CONCLUSION: Epicutaneous exposure to peanut protein can prevent induction of Oral Tolerance, and may even modify existing Tolerance to peanut. Epidermal exposure to protein allergens selectively drives Th2-type responses, and as such may promote sensitization to food proteins upon gastrointestinal exposure.
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A novel model of sensitization and Oral Tolerance to peanut protein
Immunology, 2004Co-Authors: Jessica Strid, Melanie Thomson, Jonathan Hourihane, Melanie J. Thomson, Ian Kimber, Stephenson StrobelAbstract:The prevalence of food allergic diseases is rising and poses an increasing clinical problem. Peanut allergy affects around 1% of the population and is a common food allergy associated with severe clinical manifestations. The exact route of primary sensitization is unknown although the gastrointestinal immune system is likely to play an important role. Exposure of the gastrointestinal tract to soluble antigens normally leads to a state of antigen-specific systemic hyporesponsiveness (Oral Tolerance). A deviation from this process is thought to be responsible for food-allergic diseases. In this study, we have developed a murine model to investigate immunoregulatory processes after ingestion of peanut protein and compared this to a model of Oral Tolerance to chicken egg ovalbumin (OVA). We demonstrate that Oral Tolerance induction is highly dose dependent and differs for the allergenic proteins peanut and OVA. Tolerance to peanut requires a significantly higher Oral dose than Tolerance to OVA. Low doses of peanut are more likely to induce Oral sensitization and increased production of interleukin-4 and specific immunoglobulin E upon challenge. When Tolerance is induced both T helper 1 and 2 responses are suppressed. These results show that Oral Tolerance to peanut can be induced experimentally but that peanut proteins have a potent sensitizing effect. This model can now be used to define regulatory mechanisms following Oral exposure to allergenic proteins on local, mucosal and systemic immunity and to investigate the immunomodulating effects of non-Oral routes of allergen exposure on the development of allergic sensitization to peanut and other food allergens.
Jessica Strid - One of the best experts on this subject based on the ideXlab platform.
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epicutaneous exposure to peanut protein prevents Oral Tolerance and enhances allergic sensitization
Clinical & Experimental Allergy, 2005Co-Authors: Jessica Strid, Jonathan Hourihane, Robin Callard, Ian Kimber, Stephenson StrobelAbstract:BACKGROUND: Food allergies are an important cause of life-threatening hypersensitivity reactions. Oral Tolerance can be considered the default immune response to dietary antigens, with immune deviation resulting in allergic sensitization. However, primary sensitization to food allergens may not solely be through the gastrointestinal mucosa, as strong T-helper type 2 (Th2)-biased immunity can result from exposure to protein allergens on barrier-disrupted skin. OBJECTIVE: The purpose of this study was to examine whether exposure to allergens through the skin may interfere with the normal development of Oral Tolerance and promote allergic sensitization to food proteins. METHODS: Female BALB/c mice were exposed epicutaneously to peanut protein and induction of systemic Oral Tolerance through high dose feeds of peanut protein was subsequently assessed. Other mice were rendered tolerant prior to epicutaneous peanut exposure. Sensitivity to peanut was determined by assessing delayed-type hypersensitivity, proliferative, cytokine and antibody responses. RESULTS: Epicutaneous exposure to peanut protein induced potent Th2-type immunity with high levels of IL-4 and serum IgE. Primary skin exposure prevented the subsequent induction of Oral Tolerance to peanut in an antigen-specific manner. Upon Oral challenge, mice became further sensitized and developed strong peanut-specific IL-4 and IgE responses. Furthermore, animals with existing Tolerance to peanut were partly sensitized following epicutaneous exposure. CONCLUSION: Epicutaneous exposure to peanut protein can prevent induction of Oral Tolerance, and may even modify existing Tolerance to peanut. Epidermal exposure to protein allergens selectively drives Th2-type responses, and as such may promote sensitization to food proteins upon gastrointestinal exposure.
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A novel model of sensitization and Oral Tolerance to peanut protein
Immunology, 2004Co-Authors: Jessica Strid, Melanie Thomson, Jonathan Hourihane, Melanie J. Thomson, Ian Kimber, Stephenson StrobelAbstract:The prevalence of food allergic diseases is rising and poses an increasing clinical problem. Peanut allergy affects around 1% of the population and is a common food allergy associated with severe clinical manifestations. The exact route of primary sensitization is unknown although the gastrointestinal immune system is likely to play an important role. Exposure of the gastrointestinal tract to soluble antigens normally leads to a state of antigen-specific systemic hyporesponsiveness (Oral Tolerance). A deviation from this process is thought to be responsible for food-allergic diseases. In this study, we have developed a murine model to investigate immunoregulatory processes after ingestion of peanut protein and compared this to a model of Oral Tolerance to chicken egg ovalbumin (OVA). We demonstrate that Oral Tolerance induction is highly dose dependent and differs for the allergenic proteins peanut and OVA. Tolerance to peanut requires a significantly higher Oral dose than Tolerance to OVA. Low doses of peanut are more likely to induce Oral sensitization and increased production of interleukin-4 and specific immunoglobulin E upon challenge. When Tolerance is induced both T helper 1 and 2 responses are suppressed. These results show that Oral Tolerance to peanut can be induced experimentally but that peanut proteins have a potent sensitizing effect. This model can now be used to define regulatory mechanisms following Oral exposure to allergenic proteins on local, mucosal and systemic immunity and to investigate the immunomodulating effects of non-Oral routes of allergen exposure on the development of allergic sensitization to peanut and other food allergens.