Suppression of established IgE-mediated disease

抑制已确定的 IgE 介导的疾病

• 批准号: 8239859
• 负责人: FRED Douglass FINKELMAN
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239859
• 关键词: Accident and Emergency department; Achievement; Adrenal Cortex Hormones; Adult; Affect; Affinity; Allergens; Allergic; American; Anaphylaxis; Antibodies; Antibody Suppression; Antigens; Antihistamines; Antihypertensive Agents; Asthma; Basophils; Binding; Bone Marrow; CD4 Positive T Lymphocytes; Cell Degranulation; Cells; Chronic Obstructive Airway Disease; Clinical; Data; Development; Diarrhea; Disease; Dose; Elderly; Epithelial Cells; Food; Food Hypersensitivity; Hamsters; Human; Hypersensitivity; IL-13Ralpha1; IgE; IgE Receptors; IgG1; Immunization; Immunoglobulin G; In Vitro; Incidence; Interleukin-13; Interleukin-4; Intestines; Learning; Ligands; Marrow; Mediating; Modeling; Monoclonal Antibodies; Mus; Myocardial Infarction; Patients; Pharmaceutical Preparations; Phase; Population; Prevention; Risk Factors; Rodent; Shock; Smooth Muscle Myocytes; Staging; Stroke; T-Cell Depletion; Testing; Therapeutic; Tobacco use; Vascular Endothelial Cell; Visit; Wild Type Mouse; Work; antigen challenge; cell type; cytokine; desensitization; improved; in vivo; killings; mast cell; mouse model; neutralizing antibody; novel strategies; patient population; prevent; receptor; research study; response; therapy development

DESCRIPTION (provided by applicant): This proposal will optimize 2 approaches to suppress established IgE-mediated allergy, test these approaches in a mouse model of food allergy and determine how they work. Food allergy affects 2-4% of adults and is responsible for ~30,000 emergency room visits/year in the U.S. Our VA-sponsored, mouse model studies have better defined the mechanisms responsible for food allergy and discovered approaches that can suppress established disease. Achievements include demonstrations that: 1) ingested antigen must be absorbed systemically (where it can be neutralized by IgG antibodies) to induce anaphylaxis; 2) a monoclonal antibody (mAb) to the IgE binding chain of the high affinity IgE receptor, Fc5RI1, can induce anaphylaxis, which can be prevented by a rapid desensitization approach and by pre-treatment with corticosteroids plus antihistamine; 3) anti-Fc5RI1 mAb treatment can suppress established food allergy; and 4) addition of a single dose of anti-CD4 mAb considerably enhances anti-Fc5RI1 mAb suppression of established food allergy. In addition we have developed a mouse model of anaphylaxis that utilizes IgE antibodies from human allergy patients. We will now build on these achievements by better defining the mechanisms responsible for our observations and optimizing our approaches for suppression of established food allergy. This should set the stage for applying these approaches to food-allergic humans. First, we will test the hypothesis that effects of the cytokines IL-4 and IL-13 on non-bone marrow derived cells, such as vascular endothelial cells, smooth muscle cells, and intestinal epithelial cells, are critical during the effector phase of food allergy. We will use mAbs, bone marrow IL-4 receptor 1 chain (IL-4R1) chimeric mice and mice that have deleted from specific cell types to evaluate: a) whether systemic shock and allergic diarrhea can be suppressed by treating mice with anti-IL-4R1 mAb once food allergy has become established; b) whether mice that lack IL-4 receptors on non-bone marrow-derived cells develop food-induced anaphylaxis normally; and c) whether mice that selectively lack IL-4R1 on smooth muscle cells, intestinal epithelial cells, and/or vascular endothelial cells develop food-induced anaphylaxis normally. Next, we will determine how the combination of anti-Fc5RI1 mAb and anti-CD4 mAb suppresses established food allergy and will optimize suppression of food allergy by combined mAb treatment. Although the synergistic suppression of severe, established food allergy by the combination of these two mAb results, in part, from prevention of development of anti-hamster IgG antibodies that neutralize the hamster anti-mouse Fc5RI1 mAb, the combination of anti-Fc5RI1 mAb and anti-CD4 mAb also suppresses food allergy better than anti-Fc5RI1 mAb alone prior to the development of neutralizing anti-hamster IgG antibody. We will use in vitro and in vivo experiments to determine: a) whether enhancement of anti-Fc5RI1 mAb suppression of established food allergy by anti-CD4 mAb coincides with enhanced suppression of the IL-4 and IL-13 responses to Ag challenge, enhanced suppression of mast cell degranulation, or both; b) the extent of CD4+ T cell inhibition required to enhance anti-Fc5RI1 mAb suppression of established food allergy; c) whether an anti-Fc5RI1 mAb that is not seen as foreign can completely suppress severe established food allergy in the absence of anti-CD4 mAb; and d) how the combination of anti-Fc5RI1 mAb plus anti-CD4 mAb induces long-lasting suppression of established food allergy. Our third aim will determine whether the combination of systemic immunization and IL-4R1 blockade synergistically suppresses established food allergy. Because IgG antibodies can suppress established food allergy and anti-IL-4R1 mAb can suppress IgE responses without suppressing IgG responses, we hypothesize that combining anti-IL-4R1 mAb treatment with allergen immunization will potently suppress established food allergy. Taken together, these proposed studies should provide powerful new approaches for the suppression of food allergy and other IgE-mediated disease and, by determining how these approaches work, identify ways to improve them further. PUBLIC HEALTH RELEVANCE: The VA patient population is just as susceptible as other adult Americans to anaphylaxis, but has 3 additional risk factors: 1) its large elderly population that is prescribed large numbers of therapeutic drugs; 2) its advanced age, which makes hypotensive episodes caused by anaphylaxis more likely to induce strokes and myocardial infarcts; and 3) its high incidence of tobacco use and consequent COPD, which increases the consequences of anaphylaxis-associated asthma. Results of the proposed studies that contribute to new approaches for the prevention and treatment of anaphylaxis would thus be particularly beneficial to the VA patient population. Although our study focuses on food allergy rather than drug-induced anaphylaxis, this is because food allergy is a better mouse model for IgE-mediated anaphylaxis than anaphylaxis induced by injected antigens, which can be mediated by IgG. The lessons learned from our studies should apply to all forms of IgE-mediated anaphylaxis and very likely to all forms of IgE-mediated allergy.

描述（由申请人提供）： 该建议将优化2种抑制既定的IgE介导的过敏的方法，在食物过敏的小鼠模型中测试这些方法，并确定它们的工作原理。食物过敏影响2-4％的成年人，在美国负责约30,000次急诊室就诊，我们的VA赞助的小鼠模型研究更好地定义了负责食物过敏的机制，并发现了可以抑制既定疾病的方法。成就包括：1）摄入的抗原必须被系统地吸收（可以用IgG抗体中和）以诱导过敏反应； 2）高亲和力IgE受体FC5RI1的IgE结合链的单克隆抗体（MAB）可以诱导过敏反应，可以通过快速脱敏方法和对皮质类固醇加上皮质类固醇加上抗组胺药的预处理来预防。 3）抗FC5RI1 mAb治疗可以抑制已建立的食物过敏； 4）添加单剂量的抗CD4 MAB大大增强了对已建立的食物过敏的抗FC5RI1 mAb抑制。此外，我们开发了一种过敏反应的小鼠模型，该模型利用了人类过敏患者的IgE抗体。现在，我们将通过更好地定义负责我们观察的机制并优化抑制已建立食物过敏的方法来基于这些成就。这应该为将这些方法应用于食品过敏性人体奠定了基础。首先，我们将检验以下假设：细胞因子IL-4和IL-13对非骨髓衍生细胞的影响，例如血管内皮细胞，平滑肌细胞和肠上皮细胞，在食物过敏的效应阶段至关重要。我们将使用mAbs，骨髓IL-4受体1链（IL-4R1）嵌合小鼠和已从特定细胞类型中删除的小鼠进行评估：a）a）是否可以通过使用抗-IL-4R1 MAB来抑制全身性腹泻和过敏性腹泻，一旦获得食物过敏， b）在非骨髓衍生的细胞上缺乏IL-4受体的小鼠是否会正常形成食物诱导的过敏反应； c）在平滑肌细胞，肠上皮细胞和/或血管内皮细胞上有选择性地缺乏IL-4R1的小鼠是否会正常形成食物诱导的过敏反应。接下来，我们将确定抗FC5RI1 MAB和抗CD4 MAB的组合如何抑制已建立的食物过敏，并通过联合MAB治疗优化对食物过​​敏的抑制。尽管这两个mAb结果的结合部分是由于预防抗汉堡IgG抗体的发展而抑制严重，确定的食物过敏，部分原因是抗仓鼠抗小鼠FC5RI1 mAb中和抗fc5ri1 mab和抗Cd4 mab的抗fc5ri1 mAb的组合，也比抗cd4 mab的抗衡量更好地抑制了食物的态度。中和抗汉堡IgG抗体。我们将使用体内和体内实验来确定：a）抗C5RI1 mAb抑制抗CD4 MAB对已建立的食物过敏的抑制是否与对IL-4和IL-13对AG挑战的抑制的抑制相吻合，增强了对MAST细胞降级的抑制作用，或者增强的抑制作用； b）增强抗FC5RI1 mAb抑制所需的CD4+ T细胞抑制程度 食物过敏； c）在没有抗CD4 mAb的情况下，不被视为外国的抗FC5RI1 mAb是否可以完全抑制严重的既定食物过敏； d）抗FC5RI1 MAB和抗CD4 MAB的组合如何诱导对已建立的食物过敏的长期抑制。我们的第三个目标将确定系统性免疫和IL-4R1封锁的结合是否协同抑制已建立的食物过敏。由于IgG抗体可以抑制已建立的食物过敏，而抗IL-4R1 MAB可以抑制IgE反应而无需抑制IgG反应，因此我们假设将抗IL-4R1 MAB治疗与过敏原的免疫结合在一起将迅速抑制已建立的食物过敏。综上所述，这些拟议的研究应为抑制食物过敏和其他IgE介导的疾病提供强大的新方法，并通过确定这些方法如何工作，并确定进一步改善它们的方法。 公共卫生相关性： VA患者人口与其他成年美国人对过敏反应一样容易受到敏感，但还有3个其他风险因素：1）规定大量治疗药物的老年人群； 2）其高龄，这使得由于过敏反应引起的降压发作更有可能诱导中风和心肌梗死； 3）它的烟草使用率很高及其随之而来的COPD，这增加了过敏反应相关的哮喘的后果。因此，提出的研究有助于预防和治疗过敏反应的新方法的结果对VA患者人群特别有益。尽管我们的研究侧重于食物过敏而不是药物诱导的过敏反应，但这是因为食物过敏是IgE介导的过敏反应的更好的小鼠模型，而不是由注射的抗原引起的过敏反应，这可以由IgG介导。从我们的研究中学到的经验教训应适用于所有形式的IgE介导的过敏反应，并且很可能对所有形式的IgE介导的过敏。