Developmental Immunotherapeutics of Allergic Diseases

过敏性疾病的发育免疫治疗

基本信息

批准号：
7732524
负责人：
Calman Prussin
金额：
$ 41.33万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732524
关键词：
Address Affect Allergens Allergic Amino Acids Antigen-Presenting Cells Autoimmune Diseases Basophils Binding Blood Cell Differentiation process Characteristics Clinical Clinical Trials Count Data Dendritic Cells Development Diagnosis Disease Dose Duodenum Elemental Diets Eosinophilic Esophagitis Erythema Esophageal Extrinsic asthma Flow Cytometry Food Food Hypersensitivity Frequencies Gastrointestinal Diseases Gastrointestinal tract structure Generations Host Defense Hypersensitivity Hypersensitivity skin testing IgE Immediate hypersensitivity Immune Immune response Immunologics Immunotherapeutic agent Incidence Inflammation Institution Interleukin-4 Measures Mediating Monoclonal Antibodies Other Therapy Pathogenesis Patients Play Process Production Pyloric antrum Role Score Signal Transduction Sum Surface Symptoms T-Cell Activation T-Lymphocyte Testing Th2 Cells Therapeutic Time Tissues Translating Vaccines Week Welts airborne allergen anti-IgE base concept cytokine eosinophil eosinophilic gastroenteritis food allergen immunoregulation improved in vitro Assay in vivo mast cell omalizumab response

项目摘要

Eosinophilic gastrointestinal diseases (EGIDs) are a spectrum of diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past decade, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EE). EGIDs, including eosinophilic gastroenteritis (EG) and EE, 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 EGIDs. 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? A clinical trial of omalizumab was performed 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 FcεRI 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 FcεRI 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. Omalizumab is a humanized anti-IgE monoclonal antibody approved for use in allergic asthma. Anti-IgE therapy reduces the concentration of circulating free IgE, blocks IgE binding to both FcεRI and CD23, and down regulates surface FcεRI on mast cells, basophils and dendritic cells. Because of the multiple actions of anti-IgE therapy that affect antigen presenting cells (APCs), it has been postulated that anti-IgE therapy may have immunomodulatory activity on T cells. We hypothesized two distinct mechanisms whereby anti-IgE therapy could inhibit allergen specific Th2 responses. First, anti-IgE down regulates FcεRI on dendritic cells and blocks CD23 mediated allergen binding to APCs, thereby inhibiting IgE facilitated Ag capture by APCs, which in turn could result in decreased allergen specific T cell activation. Second, IgE signaling of anti-IgE inhibits mast cell and basophil activation in vivo, which may decrease IL-4 expression, the lack of which could inhibit nave T cell differentiation into Th2 cells. To test this hypothesis, we assessed anti-IgE immunomodulation of allergen specific T cell responses during the above clinical trial of omalizumab in subjects with eosinophilic gastroenteritis and food allergy. Four allergen specific T cell responses (proliferation, dose response, precursor frequency, and cytokine expression) were measured using flow cytometry. In contradistinction to the hypothesis, we found that 16 weeks of anti-IgE therapy had no effect on allergen specific proliferation, precursor frequencies, or cytokine production, and yielded a small augmentation (not reduction) of the allergen dose response. In sum, we found no evidence to support the concept that anti-IgE therapy has an immunomodulatory or inhibitory effect on allergen specific T cells. As such, these data do not support a major role for IgE mediated Ag focusing in augmenting allergen specific T cell responses in vivo.

嗜酸性胃肠道疾病（EGID）是胃肠道嗜酸性炎症特征的疾病谱。在过去的十年中，egids的发生率急剧增加，尤其是嗜酸性食管炎（EE）。包括嗜酸性粒细胞性胃炎（例如）在内的EGID通常与食物和空气过敏元相关。大多数EGID患者都有多种食物过敏，在许多患者中，基于氨基酸的元素饮食是一种有效的治疗方法。这表明eGID发病机理是由于食物过敏原驱动的嗜酸性炎症引起的。目前，我们对我们的理解和有效治疗eGID的能力存在重大差距。为了解决治疗和发病机理问题，我们最近完成了针对嗜酸性粒细胞性胃肠炎的球核酸（治疗性单克隆抗IGE）的临床试验。这项研究提出了两个主要问题： 1。嗜酸性胃肠道疾病中临床实用性的抗IGE治疗学吗？ 2。egids的嗜酸性炎症特征是IgE依赖性过程吗？执行了一项omalizumab的临床试验，其中9名具有EGID的受试者每2周接受Omalizumab接受16周的术，而其他疗法保持恒定。血液绝对嗜酸性粒细胞计数，组织嗜酸性粒细胞计数，症状评分和自由IgE均连续测量。在基线和第16周确定嗜碱性粒细胞激活和FCεRI的过敏原皮肤测试以及流式细胞术。omalizumab在16周（34％，p = 0.004）和组合的星期12-16（42％，p = 0.012）时间点（42％，P = 0.012）时，与绝对嗜酸性粒细胞计数的降低相关。十二指肠（59％）和胃胃肠道（69％）的组织嗜酸性粒细胞降低，但没有达到统计学意义（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FcεRI表达和游离IgE均显着降低（p <0.005）。 Omalizumab提高了触发半Ximable嗜碱性激活所需的过敏原浓度，增加了170倍。过敏原的皮肤测试和红斑反应分别降低了78％和82％。症状评分在中间研究（63％）和研究结束（70％）时间点（两者的p <0.005）均降低。这些结果表明，IgE介导的过程有助于EGID中嗜酸性炎症的产生，并表明抗Ige治疗可能在这些疾病中有效。 Omalizumab是一种批准用于过敏性哮喘的人源化抗IgE单克隆抗体。抗IGE治疗降低了循环游离IgE的浓度，阻断IgE与FcεRI和CD23的结合，并下降调节在肥大细胞，嗜碱性粒细胞和树突状细胞上的表面FcεRI。由于影响抗原呈递细胞（APC）的抗IGE疗法的多种作用，因此据推测，抗IGE治疗可能对T细胞具有免疫调节活性。我们假设了两种不同的机制，可以抑制过敏原特异性TH2反应。首先，抗IgE调节在树突细胞上的FcεRI，并阻止CD23介导的过敏原与APC结合，从而抑制IgE促进APC捕获APC的AG捕获，进而导致过敏原特异性T细胞激活降低。其次，抗IgE的IgE信号传导抑制了体内肥大细胞和嗜碱性粒细胞的活化，这可能会降低IL-4表达，缺乏可能抑制T细胞中的T细胞分化为Th2细胞。为了检验这一假设，我们评估了在嗜酸性粒细胞性胃炎和食物过敏的受试者中，在上述Omalizumab的上述临床试验期间，我们评估了过敏原特异性T细胞反应的抗IGE免疫调节。使用流式细胞仪测量了四个过敏原特异性T细胞反应（增殖，剂量反应，前体频率和细胞因子表达）。与假设相反，我们发现16周的抗Ige治疗对过敏原的增殖，前体频率或细胞因子产生没有影响，并且产生了过敏原剂量反应的较小的增强（不是降低）。总而言之，我们没有发现抗Ige治疗对过敏原特异性T细胞具有免疫调节或抑制作用的概念。因此，这些数据不支持IgE介导的Ag聚焦在增强过敏原特异性T细胞反应中的主要作用。