Developmental Immunotherapeutics For Allergic Diseases And Asthma

嗜酸性粒细胞性胃肠道疾病（EGIDs）是一种以胃肠道嗜酸性粒细胞炎症为特征的疾病。在过去十年中，egid的发病率有所增加。EGIDs，包括嗜酸性胃肠炎（EG）和嗜酸性食管炎，通常与食物和空气过敏原过敏有关。大多数EGID患者都有多种食物过敏，在许多患者中，以氨基酸为基础的元素饮食是一种有效的治疗方法。这表明EGID的发病机制是由食物过敏原引起的嗜酸性炎症引起的。目前，我们对这些疾病的认识和有效治疗能力还存在较大差距。为了解决治疗和发病机制问题，我们最近完成了omalizumab（治疗性单克隆抗ige）治疗嗜酸性胃肠炎的临床试验。这项研究提出了两个主要问题：

Eosinophilic gastrointestinal diseases (EGIDs) are a spectrum of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past decade, there has been an increase in the incidence of EGIDs. EGIDs, including eosinophilic gastroenteritis (EG) and eosinophilic esophagitis, are commonly associated with food and aeroallergen hypersensitivity. Most EGID patients have numerous food allergies, and in many patients an amino acid based elemental diet is an effective treatment. This suggests that EGID pathogenesis is due to food allergen driven eosinophilic inflammation. At present, there are major gaps in our understanding of, and ability to effectively treat these diseases. To address both treatment and pathogenesis questions, we have recently completed a clinical trial of omalizumab (therapeutic monoclonal anti-IgE) for eosinophilic gastroenteritis. This study asks two major questions: 1. Are anti-IgE therapeutics of clinical utility in eosinophilic gastrointestinal diseases? 2. Is the eosinophilic inflammation characteristic of EGIDs an IgE dependent process? During the past year we completed a clinical trial of omalizumab in which 9 subjects with EGIDs received omalizumab every 2 weeks for 16 weeks while other therapy was held constant. Blood absolute eosinophil counts, tissue eosinophil counts, symptom scores, and free IgE were serially measured. Allergen skin testing, and flow cytometry for basophil activation and FceRI were determined at baseline and at week 16. Omalizumab was associated with a decrease in absolute eosinophil counts at both the 16 week (34%, p=0.004) and combined weeks 12-16 (42%, p=0.012) time points. Tissue eosinophils decreased in the duodenum (59%) and gastric antrum (69%), but did not reach statistical significance (p=0.074 and 0.098, respectively). Esophageal eosinophil counts remained unchanged. Basophil and dendritic cell FceRI expression, and free IgE were all significantly decreased (p<0.005). Omalizumab increased the concentration of allergen required to trigger half-maximal basophil activation by 170-fold. Allergen skin test wheal and erythema responses decreased by 78% and 82%, respectively. Symptom scores were decreased at both the midstudy (63%) and end of study (70%) time points (p<0.005 for both). These results demonstrate that IgE-mediated processes contribute to the generation of eosinophilic inflammation in EGIDs, and suggest that anti-IgE therapy may be effective in these disorders.