RESUMEN
BACKGROUND: Patients with food allergy produce high-titer IgE antibodies that bind to mast cells through FcεRI and trigger immediate hypersensitivity reactions on antigen encounter. Food-specific IgG antibodies arise in the setting of naturally resolving food allergy and accompany the acquisition of food allergen unresponsiveness in oral immunotherapy. OBJECTIVE: In this study we sought to delineate the effects of IgG and its inhibitory Fc receptor, FcγRIIb, on both de novo allergen sensitization in naive animals and on established immune responses in the setting of pre-existing food allergy. METHODS: Allergen-specific IgG was administered to mice undergoing sensitization and desensitization to the model food allergen ovalbumin. Cellular and molecular mechanisms were interrogated by using mast cell- and FcγRIIb-deficient mice. The requirement for FcγRII in IgG-mediated inhibition of human mast cells was investigated by using a neutralizing antibody. RESULTS: Administration of specific IgG to food allergy-prone IL4raF709 mice during initial food exposure prevented the development of IgE antibodies, TH2 responses, and anaphylactic responses on challenge. When given as an adjunct to oral desensitization in mice with established IgE-mediated hypersensitivity, IgG facilitated tolerance restoration, favoring expansion of forkhead box protein 3-positive regulatory T cells along with suppression of existing TH2 and IgE responses. IgG and FcγRIIb suppress adaptive allergic responses through effects on mast cell function. CONCLUSION: These findings suggest that allergen-specific IgG antibodies can act to induce and sustain immunologic tolerance to foods.
Asunto(s)
Alérgenos/inmunología , Hipersensibilidad al Huevo/inmunología , Tolerancia Inmunológica , Inmunoglobulina G/inmunología , Receptores de IgG/inmunología , Transducción de Señal/inmunología , Alérgenos/farmacología , Animales , Modelos Animales de Enfermedad , Hipersensibilidad al Huevo/tratamiento farmacológico , Hipersensibilidad al Huevo/genética , Hipersensibilidad al Huevo/patología , Mastocitos/metabolismo , Mastocitos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores de IgG/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Th2/inmunología , Células Th2/patologíaRESUMEN
BACKGROUND: Food allergy is a growing health problem with very limited treatment options. Investigation of the immunologic pathways underlying allergic sensitization to foods in humans has been greatly constrained by the limited availability of intestinal tissue and gut-resident immune cells. Although mouse models have offered insights into pathways of food sensitization, differences between rodent and human immune physiology limit the extension of these findings to our understanding of human disease. OBJECTIVE: We sought to develop a strategy for the generation of mice with humanized adaptive immune systems, complete with tissue engraftment by human mast cells that are competent to mount specific IgE-mediated responses and drive systemic anaphylaxis on ingestion challenge. METHODS: Nonobese diabetic severe combined immunodeficient mice lacking the cytokine receptor common gamma chain (γc-/-) and carrying a human stem cell factor transgene were engrafted with human hematopoietic stem cells. The impact of peanut (PN) feeding and IgE neutralization on the development of immune responses, mast cell homeostasis, and anaphylactic food allergy was assessed in these animals. RESULTS: Humanized nonobese diabetic severe combined immunodeficient common gamma chain-deficient stem cell factor (huNSG) mice exhibited robust engraftment with functional human T and B lymphocytes and human mast cells were found in significant numbers in their tissues, including the intestinal mucosa. Following gavage feeding with PN, they mounted specific antibody responses, including PN-specific IgE. When enterally challenged with PN, they exhibited mast-cell-mediated systemic anaphylaxis, as indicated by hypothermia and increases in plasma tryptase levels. Anti-IgE (omalizumab) treatment ablated this anaphylactic response. CONCLUSIONS: huNSG mice provide a novel tool for studying food allergy and IgE-mediated anaphylaxis.