RESUMEN
Immunoglobulin E (IgE) antibodies are known for triggering immediate hypersensitivity reactions such as food anaphylaxis. In this study, we tested whether they might additionally function to amplify nascent antibody and T helper 2 (Th2) cell-mediated responses to ingested proteins and whether blocking IgE would modify sensitization. By using mice harboring a disinhibited form of the IL-4 receptor, we developed an adjuvant-free model of peanut allergy. Mast cells and IgE were required for induction of antibody and Th2-cell-mediated responses to peanut ingestion and they impaired regulatory T (Treg) cell induction. Mast-cell-targeted genetic deletion of the FcεRI signaling kinase Syk or Syk blockade also prevented peanut sensitization. In mice with established allergy, Syk blockade facilitated desensitization and induction of Treg cells, which suppressed allergy when transferred to naive recipients. Our study suggests a key role for IgE in driving Th2 cell and IgE responses while suppressing Treg cells in food allergy.
Asunto(s)
Inmunoglobulina E/inmunología , Hipersensibilidad al Cacahuete/inmunología , Receptores de IgE/inmunología , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Alérgenos/inmunología , Animales , Desensibilización Inmunológica , Modelos Animales de Enfermedad , Inmunoglobulina E/genética , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/genética , Activación de Linfocitos/inmunología , Mastocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Hipersensibilidad al Cacahuete/genética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Receptores de IgE/antagonistas & inhibidores , Receptores de IgE/genética , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/inmunología , Transducción de Señal/inmunología , Quinasa SykRESUMEN
As the major trigger of acute allergic reactions, IgE has long been considered an ideal target for anti-allergy treatments. Omalizumab, first approved by the USA in 2003 and now in use in many other countries is a humanized monoclonal antibody that binds serum IgE. Anti-IgE therapy using omalizumab reduces circulating free IgE levels and blocks both early and late-phase reactions to allergen challenge. It has proven effective for allergic asthma and is currently being evaluated for use in a number of other atopic conditions including allergic rhinitis and chronic idiopathic urticaria. Clinical observations and mechanistic studies with omalizumab have shed new light on the multifaceted roles of IgE in immune homeostasis and in allergic disease.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antiidiotipos/farmacología , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/farmacología , Asma/tratamiento farmacológico , Homeostasis , Humanos , Inmunoglobulina E/fisiología , Mastocitos/fisiología , OmalizumabRESUMEN
BACKGROUND: Food-induced anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some subjects with significant IgE levels can ingest allergenic foods without incident. Similarly, subjects completing oral immunotherapy (OIT) tolerate food challenges despite persistent high-titer food-specific IgE. OBJECTIVE: We sought to test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis and whether this occurs through the inhibitory receptor FcγRIIb. METHODS: Food allergy-susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient (IgE(-/-)) Il4raF709 mice, which can ingest OVA without anaphylaxis, were subjected to a high-dose enteral OVA desensitization protocol (OIT). Sera from both groups were tested for the ability to activate or inhibit bone marrow mast cells (BMMCs) exposed to allergen or to passively transfer allergy to naive hosts. In parallel experiments sera obtained from patients with peanut allergy before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut-induced activation in an indirect assay by using basophils from nonallergic donors. RESULTS: Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMCs for activation by antigen challenge. Sera from Il4raF709/IgE(-/-) mice subjected to OVA OIT suppressed BMMC responses. This inhibition was IgG mediated and FcγRIIb dependent. Similarly, pre-OIT but not post-OIT sera from patients efficiently sensitized basophils for peanut-induced activation. IgG antibodies in post-OIT sera suppressed basophil activation by pre-OIT sera. This inhibition was blocked by antibodies against FcγRII. CONCLUSION: Food-specific IgG antibodies, such as those induced during OIT, inhibit IgE-mediated reactions. Strategies that favor IgG responses might prove useful in the management of food allergy.
Asunto(s)
Desensibilización Inmunológica , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/terapia , Inmunoglobulina G/inmunología , Receptores de IgG/inmunología , Administración Oral , Adolescente , Alérgenos/inmunología , Animales , Basófilos/inmunología , Niño , Femenino , Alimentos , Humanos , Hipersensibilidad Inmediata/sangre , Inmunoglobulina G/sangre , Masculino , Mastocitos/inmunología , Ratones Transgénicos , Ovalbúmina/inmunologíaAsunto(s)
Desensibilización Inmunológica/métodos , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/terapia , Exantema/etiología , Exantema/terapia , Tuberculosis Latente/tratamiento farmacológico , Rifampin/efectos adversos , Niño , Protocolos Clínicos , Contraindicaciones , Difenhidramina/administración & dosificación , Cálculo de Dosificación de Drogas , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Humanos , Tolerancia Inmunológica , Isoniazida , Tuberculosis Latente/complicaciones , Masculino , Rifabutina/uso terapéuticoRESUMEN
BACKGROUND: As there is limited data on the sustainability of desensitization of multifood-oral immunotherapy (multifood-OIT), we conducted a multisite multifood-OIT study to compare the efficacy of successful desensitization with sustained dosing vs discontinued dosing after multifood-OIT. METHODS: We enrolled 70 participants, aged 5-22â¯years with multiple food allergies confirmed by double-blind placebo-controlled food challenges (DBPCFCs). In the open-label phase of the study, all participants received omalizumab (weeks 1-16) and multi-OIT (2-5 allergens; weeks 8-30) and eligible participants (on maintenance dose of each allergen by weeks 28-29) were randomized 1:1:1 to 1â¯g, 300â¯mg, or 0â¯mg arms (blinded, weeks 30-36) and then tested by food challenge at week 36. Success was defined as passing 2â¯g food challenge to at least 2 foods in week 36. FINDINGS: Most participants were able to reach a dose of 2â¯g or higher of each of 2, 3, 4, and 5 food allergens (as applicable to the participant's food allergens in OIT) in week 36 food challenges. Using an intent-to-treat analysis, we did not find evidence that a 300â¯mg dose was effectively different than a 1â¯g dose in maintaining desensitization, and both together were more effective than OIT discontinuation (0â¯mg dose) (85% vs 55%, Pâ¯=â¯0.03). Fifty-five percent of the intent-to-treat participants and 69% of per protocol participants randomized to the 0â¯mg arm showed no objective reactivity after 6â¯weeks of discontinuation. Cross-desensitization was found between cashew/pistachio and walnut/pecan when only one of the foods was part of OIT. No statistically significant safety differences were found between the three arms. INTERPRETATION: These results suggest that sustained desensitization after omalizumab-facilitated multi-OIT best occurs through continued maintenance OIT dosing of either 300â¯mg or 1â¯g of each food allergen as opposed to discontinuation of multi-OIT. FUNDING: Sean N. Parker Center for Allergy and Asthma Research at Stanford University, Jeff and MacKenzie Bezos, NIAID AADCRC U19AI104209. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT02626611.
RESUMEN
The syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) is a subphenotype of the polycystic ovary syndrome. It is one of the most common causes of menstrual problems, hyperandrogenic symptoms, and insulin resistance among young women. Review of clinical data in an outpatient adolescent clinic showed that of the 1,002 young women (ages 10-21 years) attending the clinic over a 2-year period, 50 (5%) were diagnosed with HAIR-AN syndrome. Mean age of the patients was 15.5, initial mean weight at diagnosis was 94.5 kg, and the mean BMI was 33.33 kg/m2. Patients were treated with a weight-stabilization and -reduction program, oral contraceptive pills, and in most cases metformin. Of the patients, 80% were compliant with the follow-up and treatment regimen, 60% maintained or reduced their weight, 95% had regular menstrual cycles, and in most patients, the acne and/or hirsutism were the same or better than at the start of treatment. We conclude that HAIR-AN syndrome is a common disease in young women and multifaceted, aggressive treatment appears to be effective in reducing the severity of symptoms and preventing further consequences.
Asunto(s)
Anomalías Múltiples/diagnóstico , Acantosis Nigricans/diagnóstico , Hiperandrogenismo/diagnóstico , Resistencia a la Insulina/fisiología , Anomalías Múltiples/dietoterapia , Anomalías Múltiples/tratamiento farmacológico , Acantosis Nigricans/dietoterapia , Acantosis Nigricans/tratamiento farmacológico , Adolescente , Adulto , Niño , Terapia por Ejercicio , Femenino , Humanos , Hiperandrogenismo/dietoterapia , Hiperandrogenismo/tratamiento farmacológico , Estudios Retrospectivos , SíndromeRESUMEN
The transdermal contraceptive patch, Ortho Evra, was approved in December 2001 and released on the market in June 2002. In this study, we reviewed clinical data of young women who started the patch between June 2002 and December 2003 in the adolescent medicine clinic at a university-based outpatient center. A total of 62 patients started the patch in that period and two of them were lost to follow-up. Mean age of patients was 17.9 years and mean length of use was 10 cycles. Only 10 patients (16.7%) discontinued use. Reasons for discontinuation were moderate to severe skin irritation (3 patients, 5%), complete detachment (3 patients, 5%), and economic reasons (4 patients, 6.7%). Compliance was excellent overall and the side-effects profile was good. No pregnancies occurred during this period. These results confirmed that the transdermal contraceptive patch is easy to use and an effective method of birth control that may be better tolerated by young women. It also seemed to improve contraceptive compliance in this population.