Maternal transfer of protection from allergic gastrointestinal disease

母体传递预防过敏性胃肠道疾病的保护

• 批准号: 7640742
• 负责人: Lynn Puddington
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-18 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640742
• 关键词: Activities of Daily Living; Adult; Affect; Agreement; All-Trans-Retinol; Allergens; Allergic; Antibodies; Antigen-Presenting Cells; Antigens; Applications Grants; Attenuated; B-Lymphocytes; Biological; Biology; Breast Feeding; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Child; Data; Development; Diarrhea; Diet; Dietary Fats; Discipline of Nursing; Disease; Disease susceptibility; Dose; Down-Regulation; Epidemiologic Studies; Fat-Soluble Vitamin; Food; Food Hypersensitivity; Gastrointestinal Diseases; Gastrointestinal tract structure; Generations; Goals; Health; Homing; Human Milk; IgE; Immune; Immune response; Immune system; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Knowledge; Lactation; Life; Link; Location; Mediating; Memory B-Lymphocyte; Mesentery; Modeling; Mother-Child Relations; Mothers; Mus; Neonatal; Nurses; Outcome; Ovalbumin; Phenotype; Population; Predisposition; Prevalence; Prevention; Public Health; Research Project Grants; Resolution; Role; Site; T-Cell Proliferation; T-Lymphocyte; Transgenic Mice; Tretinoin; Vitamin A; Weaning; allergic airway disease; attenuation; base; cytokine; desensitization; design; feeding; food allergen; improved; in vivo; in vivo Model; lymph nodes; macrophage; mouse model; neonate; offspring; oral tolerance; prevent; pup; response; transmission process

DESCRIPTION (provided by applicant): The strategy of feeding large doses of antigen to prevent or reverse intestinal inflammatory diseases has not been as successful as was anticipated. This should not eliminate consideration of allergen desensitization by induction of oral tolerance as a mechanism to prevent allergic gastrointestinal disease in response to food antigens. Our preliminary data demonstrate that low dose of antigen delivered from mother to child in breast milk induces antigen-specific Tregs in gut-draining lymph nodes. Perhaps the acquisition of antigen from breast milk provides the perfect context (i.e. TGF¿ and retinoic acid) to result in focused protection by Treg in the exact site where it is needed, the gastrointestinal tract. The goals of this grant application are to further the understanding of how breast milk transmission of antigen elicits mucosal Treg responses, and to determine the potential of breast-milk antigen induced Tregs to influence allergic responses to food antigens in the intestine. It has been recently determined that retinoic acid enhances TGF¿-dependent differentiation of na¿ve CD4+ T cells into FosP3+ Tregs and directs their homing to the gut. One of the major functions of breast milk and breast milk macrophages is to deliver dietary lipids and fat-soluble vitamins (e.g. vitamin A [retinol] and its metabolites) to nursing offspring. Moreover, vitamin A levels in the maternal diet are known to affect development of the immune system in breastfed neonates. Thus, we hypothesize that during breastfeeding, offspring acquire allergen which elicits CD4+ T responses under the influence of breast milk TGF¿ and maternal vitamin A, inducing antigen-specific Tregs in the neonatal gastrointestinal tract. We propose that this maternal transfer mechanism to elicit Tregs could mediate antigen-specific protection from allergic gastrointestinal disease in offspring. To explore the validity of this hypothesis and to determine its biological relevance, we propose the following Aims: SPECIFIC AIM 1. Determine the capacity of breast milk to induce antigen-specific Tregs via delivery of retinoic acid (TGF¿ and allergen) to the neonatal gastrointestinal tract; and SPECIFIC AIM 2. Determine the capacity of breast milk antigen induced Tregs to suppress intestinal inflammation in vivo using a model of food allergen induced diarrhea. If we find that this maternal breast milk antigen-induced population of Tregs survives after weaning and is functional in suppressing food allergy, it will be important to consider what appears to be a safe strategy for mothers to induce protective immune responses in their offspring. Mothers, particularly those that are nursing, are highly motivated to improve the health of their children. If it is possible to modify breast milk content to enhance development of mucosal tolerance in neonates, this could be an effective strategy to prevent or attenuate immune-mediated inflammatory diseases in the intestine. The relevance of this project to public health is based on the fact that the prevalence of food allergy appears to be increasing; yet there are no definitive therapies. This exploratory project aims to define whether induced oral tolerance in neonates can provide long term protection from inflammatory responses to food allergens in the gut. The strategy is based on the concept that the best way to prevent detrimental immune responses to food is to maximize desensitization to allergens as early in life as possible, before pathogenic antigen-specific T and B cell memory is established.

描述（由申请人提供）：喂养大剂量抗原以预防或逆转肠道炎症性疾病的策略并不像预期的那样成功。这不应排除通过诱导口服耐受性的过敏原脱敏作为预防食物抗原引起的过敏性胃肠道疾病的一种机制的考虑。我们的初步数据表明，母乳中低剂量的抗原从母亲传递给孩子，诱导肠道引流淋巴结中的抗原特异性T淋巴细胞。也许从母乳中获得抗原提供了完美的环境（即TGF β和视黄酸），从而在需要的确切部位（胃肠道）产生Treg的集中保护。这项资助申请的目的是进一步了解母乳抗原传播如何激发粘膜Treg反应，并确定母乳抗原诱导的Treg影响肠道中食物抗原过敏反应的潜力。最近已经确定，视黄酸增强幼稚CD 4 + T细胞向FosP 3 + T细胞的TGF β依赖性分化，并指导它们归巢到肠道。母乳和母乳巨噬细胞的主要功能之一是将膳食脂质和脂溶性维生素（例如维生素A [视黄醇]及其代谢物）输送给哺乳后代。此外，已知母亲饮食中的维生素A水平会影响母乳喂养的新生儿免疫系统的发育。因此，我们假设，在母乳喂养期间，后代获得过敏原，在母乳TGF β和母体维生素A的影响下激发CD 4 + T反应，在新生儿胃肠道中诱导抗原特异性T细胞。我们认为，这种母体转移机制，以引发TdR可以介导抗原特异性保护过敏性胃肠道疾病的后代。为了探索这一假设的有效性，并确定其生物学相关性，我们提出了以下目标：具体目标1。确定母乳通过向新生儿胃肠道递送视黄酸（TGF β和过敏原）诱导抗原特异性THBE的能力;和特异性目的2。使用食物过敏原诱导的腹泻模型确定母乳抗原诱导的THBE在体内抑制肠道炎症的能力。如果我们发现这种母乳抗原诱导的Teptide群体在断奶后存活，并且在抑制食物过敏中起作用，那么考虑母亲在其后代中诱导保护性免疫应答的安全策略将是重要的。母亲，特别是哺乳期的母亲，非常积极地改善子女的健康。如果有可能改变母乳含量以增强新生儿粘膜耐受性的发展，这可能是预防或减轻肠道免疫介导的炎症性疾病的有效策略。该项目与公共卫生的相关性是基于这样一个事实，即食物过敏的患病率似乎正在增加;但没有确定的治疗方法。该探索性项目旨在确定新生儿诱导的口服耐受是否可以提供长期保护，以防止肠道中食物过敏原的炎症反应。该策略基于这样的概念，即防止对食物的有害免疫反应的最佳方式是在生命的早期，在致病性抗原特异性T和B细胞记忆建立之前，尽可能地使对过敏原的脱敏最大化。