Controlling Allergen-specific Th2-type Responses by Targeting DC Surface Lectins

通过靶向 DC 表面凝集素来控制过敏原特异性 Th2 型反应

基本信息

批准号：
8358464
负责人：
SangKon Oh
金额：
$ 19.6万
依托单位：
BAYLOR RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8358464
关键词：
Age Allergens Allergic Allergic Disease Allergic rhinitis Ambrosia Animals Antigen-Presenting Cells Antigens Basophils Biopsy CD4 Positive T Lymphocytes Caring Cell Wall Cell surface Clinical Research Commit Complex Data Dendritic Cells Dermatitis Development Dose Effectiveness Enzyme-Linked Immunosorbent Assay Extrinsic asthma Functional disorder Future Genetic Predisposition to Disease Glucans House Dust Mite Allergens Human Hypersensitivity skin testing IgE Immune Immune System Diseases Immune response Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunoglobulins Immunotherapeutic agent Immunotherapy In Vitro Individual Infiltration Lead Lectin Ligands Long-Term Effects Lymphocyte Macaca mulatta Mediating Memory Modeling Pathway interactions Patients Peripheral Blood Mononuclear Cell Polymers Route Serum Shapes Skin Staining method Stains T cell response T-Lymphocyte Testing Therapeutic Tissues Toxic effect Vaccines Work atopy cell type clinical efficacy curdlan cytokine dectin 1 design eosinophil in vivo mast cell migration neutralizing monoclonal antibodies nonhuman primate novel novel therapeutics receptor research study response socioeconomics treatment duration treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Controlling allergen-specific Th2-type responses by targeting DC surface lectins (PI: Oh, SangKon) Increasing numbers of patients with allergic diseases demand safe and long-term effective therapeutics. Allergen-induced pathogenic immune responses are the major cause of multiple types of allergic diseases, including allergic atopy, dermatitis, allergic rhinitis, and allergic asthma. The pathophysiology of such allergic immune disorders is complex and is often associated with several factors (e.g., genetic susceptibility, age, and route and dose of allergen exposure). However, studies in the past have revealed that allergen-specific Th2-type immune responses are directly associated with the development of such allergen-induced immune disorders. Therefore, therapeutic approaches with immune modifiers of the Th2 pathway represent a rational strategy for the treatment of such allergic diseases. However, current strategies targeting individual effector molecules (e.g., receptor antagonists and soluble receptors as well as neutralizing monoclonal antibodies (mAbs) to Th2 cytokines) may be insufficient to resolve the complex and multiple-effector-driven allergic immune disorders. Although specific immunotherapy (SIT) has been a hallmark of care among allergists for decades, considerable controversy still remains regarding its clinical efficacy, period of treatment, and socioeconomic consequences. We have recently found that human dendritic cells (DCs; the major immune inducers and controllers) activated via Dectin-1 with components of bacterial cell wall can significantly down-regulate Th2-type immune responses in our in vitro experiments using peripheral blood mononuclear cells from allergic patients. Thus, we surmise that activation of patient DCs via Dectin-1 can effectively control the pathogenic Th2-type immune responses in patients. This strategy targets Th2-type T cells, and thus it is expected to be more efficient than blocking one or two effector molecules secreted from the pathogenic Th2-type T cells. Furthermore, our immunotherapeutic strategy could bring long-term effects by reprogramming the quality of the pathogenic Th2-type T cells toward other cell types. To develop a novel human immunotherapeutic for such allergic immune disorders, we have generated an agonistic anti-human Dectin-1 mAb which cross-reacts with Dectin-1 in non-human primates (NHP). In this study, we propose to test the effectiveness of anti-hDectin-1 mAb in controlling Th2-type T cell responses followed by decreased IgE responses in both human in vitro (in Aim 1) and NHP in vivo (in Aim 2) using patient PBMCs and an NHP model of allergic atopy, respectively. At the end of this exploratory study (R21), we will be able to determine: The effectiveness of anti-hDectin-1 mAb treatment in human in vitro and NHP in vivo. This will lead us 1) to further study the effectiveness of anti-hDectin-1 mAb in broader ranges of allergic diseases, 2) to humanize anti-hDectin-1 mAb for toxicity and clinical studies in the near future, and 3) to design new and effective vaccine strategies that can bring long-term benefits to many allergic patients in the near future. PUBLIC HEALTH RELEVANCE: Increasing numbers of patients with Th2-driven allergic diseases highly demands effective therapeutics. This work tests a novel immunotherapeutic strategy that can control pathogenic Th2-type immune responses by targeting receptors expressed on major immune inducers and controllers, e.g. dendritic cells. The results of this study will have immediate implications for the rational design and development of effective immunotherapeutic and vaccines for several types of allergen-induced immune disorders. 1

描述（由申请人提供）：通过靶向DC表面凝集素（PI：OH，Sangkon）来控制过敏原特异性Th2型反应，从而增加了过敏性疾病的患者数量增加，需要安全且长期有效的治疗疗法。过敏原诱导的致病性免疫反应是多种类型的过敏性疾病的主要原因，包括过敏性特应性，皮炎，过敏性鼻炎和过敏性哮喘。这种过敏性免疫疾病的病理生理很复杂，通常与多种因素有关（例如，过敏原暴露的遗传易感性，年龄，途径以及剂量）。但是，过去的研究表明，过敏原特异性Th2型免疫反应与这种过敏原诱导的免疫疾病的发展直接相关。因此，具有TH2途径的免疫修饰剂的治疗方法代表了治疗此类过敏性疾病的合理策略。但是，针对个体效应分子的当前策略（例如受体拮抗剂和可溶性受体以及中和单克隆抗体（对Th2细胞因子）中和的策略可能不足以解决复杂的和多效应器驱动的过敏性免疫疾病。尽管特定的免疫疗法（SIT）数十年来一直是过敏症患者护理的标志，但关于其临床疗效，治疗期和社会经济后果仍然存在很大的争议。我们最近发现，通过Dectin-1用细菌细胞壁成分激活的人树突状细胞（DC；主要的免疫诱导剂和控制剂）可以在我们的体外实验中使用外周血单核细胞中的体外实验中显着下调Th2型免疫反应。因此，我们推测，通过Dectin-1激活患者DC可以有效控制患者的致病性Th2型免疫反应。该策略靶向Th2型T细胞，因此预计它比阻止从致病性Th2型T细胞中分泌的一个或两个效应分子更有效。此外，我们的免疫治疗策略可以通过将致病性Th2型T细胞的质量重新编程为其他细胞类型来带来长期影响。为了为这种过敏性免疫疾病开发一种新型的人类免疫治疗性，我们产生了一种激动的抗人Dectin-1 MAB，该抗人类Dectin-1 MAB在非人类灵长类动物（NHP）中与Dectin-1交叉反应。在这项研究中，我们建议测试抗HDectin-1 MAB在控制人体体外（在AIM 1）和使用患者PBMC的NHP（在AIM 2中）和NHP的NHP NHP模型的NHP模型的抗HDectin-1 MAB在控制Th2型T细胞反应中的有效性。在这项探索性研究结束时（R21），我们将能够确定：抗HDECTIN-1 MAB治疗在人体体外和NHP中的有效性。这将导致我们1）进一步研究抗HDectin-1 MAB在更广泛的过敏性疾病范围内的有效性，2）在抗Hdectin-1 MAb中人性化毒性和临床研究不久的将来，以及3）设计新的有效疫苗策略，可以在不久的将来为许多过敏患者带来长期利益。公共卫生相关性：越来越多的Th2驱动过敏性疾病的患者高度要求有效的治疗剂。这项工作测试了一种新型的免疫治疗策略，可以通过针对以主要免疫诱导剂和控制剂（例如树突状细胞。这项研究的结果将对几种类型的过敏原诱导的免疫疾病的有效的免疫治疗和疫苗的合理设计和开发具有直接的影响。 1