Developmental Immunotherapeutics For Allergic Diseases And Asthma

嗜酸性粒细胞性胃肠道疾病（EGID）是一系列以胃肠道嗜酸性粒细胞炎症为特征的疾病。在过去的十年中，EGID的发病率有所增加。EGID，包括嗜酸性粒细胞性胃肠炎（EG）和嗜酸性粒细胞性食管炎，通常与食物和吸入过敏原过敏相关。大多数EGID患者有许多食物过敏，在许多患者中，基于氨基酸的元素饮食是有效的治疗方法。这表明EGID发病机制是由于食物过敏原驱动的嗜酸性粒细胞炎症。目前，我们对这些疾病的理解和有效治疗这些疾病的能力存在重大差距。为了解决治疗和发病机制问题，我们最近完成了奥马珠单抗（治疗性单克隆抗IgE）治疗嗜酸性粒细胞性胃肠炎的临床试验。这项研究提出了两个主要问题： 1.抗IgE药物在嗜酸性粒细胞性胃肠疾病中是否具有临床应用价值？ 2.嗜酸性粒细胞性炎症是EGIDs的特征性IgE依赖性过程吗？ 在过去的一年中，我们完成了一项奥马珠单抗的临床试验，其中9名EGID受试者每2周接受奥马珠单抗治疗，持续16周，而其他治疗保持不变。连续测量血液嗜酸性粒细胞绝对计数、组织嗜酸性粒细胞计数、症状评分和游离IgE。在基线和第16周测定变应原皮肤试验和流式细胞术的嗜碱性粒细胞活化和FceRI。奥马珠单抗与第16周（34%，p=0.004）和第12-16周（42%，p=0.012）时间点的嗜酸性粒细胞绝对计数降低相关。十二指肠（59%）和胃窦（69%）的组织嗜酸性粒细胞减少，但未达到统计学显著性（分别为p=0.074和0.098）。食管嗜酸性粒细胞计数保持不变。嗜碱性粒细胞和树突状细胞FceRI表达以及游离IgE均显著降低（p<0.005）。奥马珠单抗使触发半数最大嗜碱性粒细胞活化所需的过敏原浓度增加了170倍。过敏原皮肤试验风团和红斑反应分别减少了78%和82%。症状评分在研究中期（63%）和研究结束（70%）时间点均降低（两者均为p<0.005）。这些结果表明，IgE介导的过程有助于EGID中嗜酸性粒细胞炎症的产生，并表明抗IgE治疗可能对这些疾病有效。

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.