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

描述（由申请人提供）：通过靶向DC表面凝集素控制过敏原特异性th2型反应（PI: Oh, SangKon）越来越多的过敏性疾病患者需要安全和长期有效的治疗方法。过敏原诱导的致病性免疫反应是多种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是复杂的，通常与几个因素有关（例如，遗传易感性、年龄、过敏原暴露的途径和剂量）。然而，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，使用Th2途径的免疫调节剂的治疗方法代表了治疗此类过敏性疾病的合理策略。然而，目前针对单个效应分子（例如受体拮抗剂和可溶性受体以及中和Th2细胞因子的单克隆抗体）的策略可能不足以解决复杂的多效应驱动的过敏性免疫疾病。尽管特异性免疫疗法（SIT）几十年来一直是过敏症专家治疗的一个标志，但关于其临床疗效、治疗期和社会经济后果仍存在相当大的争议。最近，我们利用过敏患者外周血单个核细胞进行体外实验，发现通过Dectin-1与细菌细胞壁组分激活的人树突状细胞（dc，主要的免疫诱导剂和控制者）可以显著下调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。该策略以th2型T细胞为靶点，因此预期比阻断致病性th2型T细胞分泌的一两个效应分子更有效。此外，我们的免疫治疗策略可以通过将致病性th2型T细胞的质量重编程为其他细胞类型而带来长期效果。为了开发一种新的人类免疫治疗方法来治疗这种过敏性免疫疾病，我们在非人灵长类动物（NHP）中产生了一种与Dectin-1交叉反应的激动性抗人Dectin-1单抗。在这项研究中，我们提出分别使用患者pbmc和NHP变态反应性模型，测试抗hdectin -1 mAb在体外（Aim 1）和体内（Aim 2）控制th2型T细胞反应后降低IgE反应的有效性。在这项探索性研究结束时（R21），我们将能够确定：抗hdectin -1 mAb在体外治疗人类和体内治疗NHP的有效性。这将导致我们1)进一步研究抗hdectin -1单抗在更广泛的过敏性疾病中的有效性，2)人源化抗hdectin -1单抗在过敏性疾病中的毒性和临床研究

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