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

• 批准号: 8497621
• 负责人: SangKon Oh
• 金额: $ 23.29万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8497621
• 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

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.

描述(由申请人提供)：通过靶向DC表面凝集素(PI：OH，SangKon)控制过敏原特异性Th2型反应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学是复杂的，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，过敏原特异性的Th2型免疫反应与此类过敏原诱导的免疫紊乱的发生直接相关。因此，使用Th2途径的免疫调节剂的治疗方法是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(如受体拮抗剂和可溶性受体以及中和抗Th2细胞因子的单抗)的策略可能不足以解决复杂和多效应驱动的变态反应性免疫疾病。尽管几十年来，特异性免疫疗法(SIT)一直是过敏专科医生关注的一个标志，但关于其临床疗效、治疗周期和社会经济后果，仍存在相当大的争议。我们最近发现，由Dectin-1激活的含有细菌细胞壁成分的人树突状细胞(DC；主要的免疫诱导器和控制器)在我们使用过敏患者外周血单核细胞的体外实验中可以显著下调Th2型免疫反应。因此，我们推测，通过Dectin-1激活患者DC可以有效地控制患者致病的Th2型免疫反应。这一策略针对Th2型T细胞，因此预计它比阻断致病Th2型T细胞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Th2型T细胞的质量重新编程为其他类型的细胞来带来长期效果。为了开发一种新的人类免疫疗法来治疗这种过敏性免疫疾病，我们产生了一种激动型抗人Dectin-1单抗，它与Dectin-1在非人灵长类动物(NHP)中发生交叉反应。在这项研究中，我们建议分别使用患者PBMC和NHP过敏性特应性模型来测试抗hDectin-1单抗控制Th2型T细胞应答的有效性，以及在体外(AIM 1)和NHP体内(AIM 2)中抑制IgE应答的效果。在这项探索性研究(R21)结束时，我们将能够确定：抗hDectin-1单抗在体外对人的治疗效果，在体内对NHP的治疗效果。这将使我们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单抗用于毒性和临床研究 3)设计新的有效的疫苗策略，在不久的将来可以为许多过敏患者带来长期好处。