Maternal transfer of protection from allergic gastrointestinal disease

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。这不能排除通过诱导口服耐受来实现过敏原脱敏的可能性，因为这是预防食物抗原引起的过敏性胃肠道疾病的一种机制。我们的初步数据表明，低剂量的抗原通过母乳从母亲传递给孩子，在肠引流淋巴结诱导抗原特异性treg。也许从母乳中获得抗原提供了完美的环境（即TGF¿和视黄酸），从而导致Treg在需要它的确切位置（胃肠道）集中保护。本基金申请的目的是进一步了解母乳中抗原的传播如何引起粘膜Treg反应，并确定母乳中抗原诱导的Treg影响肠道中对食物抗原的过敏反应的潜力。最近已经确定维甲酸可以增强TGF依赖的CD4+ T细胞向FosP3+ treg的分化，并引导它们归巢到肠道。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（如维生素A[视黄醇]及其代谢物）输送给哺乳的后代。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过程中，子代获得过敏原，在母乳TGF -¿和母体维生素A的影响下，引起CD4+ T反应，在新生儿胃肠道中诱导抗原特异性Tregs。我们认为，这种诱导Tregs的母体转移机制可能介导了后代对过敏性胃肠道疾病的抗原特异性保护。为了探索这一假设的有效性并确定其生物学相关性，我们提出以下目标：确定母乳通过向新生儿胃肠道输送视黄酸（TGF¿和过敏原）诱导抗原特异性Tregs的能力；2.具体目标利用食物过敏原诱导腹泻模型，在体内确定母乳抗原诱导Tregs抑制肠道炎症的能力。如果我们发现母乳抗原诱导的Tregs在断奶后存活，并具有抑制食物过敏的功能，那么考虑母亲在其后代中诱导保护性免疫反应的安全策略将是重要的。母亲，特别是哺乳期的母亲，有很大的动力去改善她们孩子的健康。如果有可能通过改变母乳含量来增强新生儿粘膜耐受性的发育，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以下事实：食物过敏的患病率似乎正在上升；然而，目前还没有明确的治疗方法。这个探索性项目旨在确定新生儿诱导的口服耐受是否可以长期保护肠道中食物过敏原的炎症反应。该策略基于这样一个概念，即防止对食物产生有害免疫反应的最佳方法是，在致病性抗原特异性T细胞和B细胞记忆建立之前，尽可能早地对过敏原进行最大程度的脱敏。

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.