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

描述（由申请人提供）：通过靶向DC表面凝集素控制变应原特异性Th 2型应答（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类型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学是复杂的，并且通常与几种因素（例如，遗传易感性、年龄以及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Th 2型免疫应答与这种过敏原诱导的免疫疾病的发展直接相关。因此，使用Th 2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，目前靶向单个效应分子（例如，受体拮抗剂和可溶性受体以及针对Th 2细胞因子的中和性单克隆抗体（mAb））可能不足以解决复杂和多效应物驱动的过敏性免疫病症。尽管特异性免疫疗法（SIT）几十年来一直是过敏症专家的标志性治疗，但关于其临床疗效、治疗时间和社会经济后果仍存在相当大的争议。我们最近发现，通过Dectin-1与细菌细胞壁的成分激活的人树突状细胞（DC;主要的免疫诱导剂和控制器）可以显着下调Th 2型免疫应答，在我们的体外实验中使用外周血单核细胞过敏患者。因此，我们推测通过Dectin-1激活患者DC可以有效地控制患者中的致病性Th 2型免疫应答。该策略靶向Th 2型T细胞，因此预期其比阻断从致病性Th 2型T细胞分泌的一种或两种效应分子更有效。此外，我们的免疫策略可以通过将致病性Th 2型T细胞的质量重新编程为其他细胞类型来带来长期效果。为了开发用于这种过敏性免疫病症的新型人免疫原，我们已经产生了激动性抗人Dectin-1 mAb，其在非人灵长类动物（NHP）中与Dectin-1交叉反应。在这项研究中，我们提出测试抗hDectin-1单克隆抗体在控制Th 2型T细胞反应，然后降低IgE反应在人体体外（目的1）和NHP在体内（目的2）分别使用患者PBMC和过敏性特应性的NHP模型的有效性。在本探索性研究（R21）结束时，我们将能够确定：抗hDectin-1 mAb治疗在体外人体和体内NHP中的有效性。这将引导我们1）进一步研究抗hDectin-1 mAb在更广泛范围的过敏性疾病中的有效性，2）人源化抗hDectin-1 mAb用于过敏性疾病中的毒性和临床研究。 3）设计新的有效的疫苗策略，在不久的将来为许多过敏患者带来长期益处。

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.