Inhalation Tolerance, IgE and gamma/delta T cells

吸入耐受性、IgE 和 γ/δ T 细胞

• 批准号: 8243337
• 负责人: WILLI K BORN
• 金额: $ 23.78万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-07 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243337
• 关键词: Address; Allergens; Allergic Disease; Allergic Reaction; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Blood Circulation; Breathing; Cell Communication; Cell physiology; Cells; Data; Dendritic Cells; Development; Employment; Human; IgE; Immune System Diseases; Immunoglobulin G; Immunoglobulin Switch Recombination; Immunotherapy; Interferons; Interleukin-12; Interleukin-17; KAI1 gene; Knowledge; Lead; Left; Link; Lung; Mediating; Mediator of activation protein; Membrane; Methods; Molecular; Mus; Pathway interactions; Preparation; Process; Protocols documentation; Regulation; Reporting; Signal Transduction; Specificity; Spleen; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Vesicle; allergic response; cell type; cytokine; in vitro Assay; in vivo; mouse model; pathogen; prevent; research study; response

DESCRIPTION (provided by applicant): Immunological tolerance through mucosal antigen exposure is allergen-specific, highly effective and long lasting. Although such features should make it suitable for the treatment of immunological diseases, current protocols of specific immunotherapy rarely take advantage of it. Better knowledge of the mechanisms might simplify treatments and help avoid potentially dangerous exposures. It is known that mucosal tolerance to inhaled antigens can be mediated by 34 T cells. In cell transfer experiments in mice, splenic 34 T cells from donors tolerized by repeated antigen inhalation were shown to suppress the IgE response to the antigen with surprisingly high efficiency, while leaving IgG levels unchanged. Although 34 T cells are not normally selected by conventional antigens, the IgE suppression appeared to be antigen-specific, but the underlying mechanism was not determined. We have characterized the IgE suppressive 34 T cells in the spleen, and our preliminary data now provide direct support for their antigen-specificity. Moreover, our new data suggest that these 34 T cells are induced by splenic dendritic cells (DCs), and function themselves as antigen presenting cells (APCs), preventing the development of T helper 2 (Th2) cells. We hypothesize that the ability of 34 T cells to regulate T-dependent specific IgE antibodies is directly linked to their inducible antigen presenting function. Specifically, we now envisage a pathway in which inhaled antigen, initially absorbed in the lung, is released into the circulation, retrieved in the spleen and, along with activating signals, passed on by splenic dendritic cells (DCs) to splenic 34 T cells, which differentiate into APCs. Dictated by their own functional bias, the 34 T cell-APCs then modulate T-dependent Ig switch recombination in B cells. The 34 T cells of the IgE suppressor-type in this study (V34+CD82+IFN-3+) reduce specific IgE antibody. We propose to test this hypothesis and investigate the processes involved by determining whether antigen is transferred to the IgE regulatory 34 T cells, and if these cells can function as APCs for the inhaled antigen. We will also determine whether inhalation-induced IgE suppressive 34 T cells regulate antigen-specific Th2 differentiation, and if IFN-3 is a crucial mediator in their regulatory control. Finally, we will examine if the IgE-regulatory function of the 34 T cells, which requires induction by MyD88+ DCs, relies on Th1-inducing cytokines produced by these DCs, such as IL-12. These studies should provide a better understanding of natural, 34 T cell-mediated, control mechanisms in allergic responses, and their potential uses for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Human protection against parasitic pathogens partially relies on antibodies known as IgE. Unfortunately, IgE antibodies also mediate harmful allergic reactions to inert environmental substances known as allergens. However, repeated inhalation of allergens can induce a state of tolerance and prevent later allergic reactions. The underlying mechanism is not yet well understood. In this application, we propose to investigate the action of a distinct cell type, known as 34 T cell, which, following allergen inhalation, can prevent development of IgE antibodies. Our planned experiments should reveal how the regulatory function of these 34 T cells is induced, and determine how they exert their regulatory control. This new information about 34 T cell functions in IgE regulation will be helpful in developing better approaches to the control of IgE in allergic diseases.

描述（由申请方提供）：通过粘膜抗原暴露产生的免疫耐受具有过敏原特异性、高效性和持久性。尽管这些特征使其适合于治疗免疫性疾病，但目前的特异性免疫治疗方案很少利用它。更好地了解其机制可能会简化治疗，并有助于避免潜在的危险暴露。已知粘膜对吸入抗原的耐受性可由34 T细胞介导。在小鼠的细胞转移实验中，来自通过反复抗原吸入耐受的供体的脾34 T细胞显示出以令人惊讶的高效率抑制对抗原的IgE应答，同时保持IgG水平不变。尽管34 T细胞通常不被常规抗原选择，但IgE抑制似乎是抗原特异性的，但其潜在机制尚未确定。我们已经表征了脾脏中IgE抑制性34 T细胞，并且我们的初步数据现在为它们的抗原特异性提供了直接支持。此外，我们的新数据表明，这34个T细胞由脾树突状细胞（DC）诱导，并作为抗原呈递细胞（APC）发挥作用，阻止辅助性T细胞2（Th 2）的发育。我们假设34 T细胞调节T依赖性特异性IgE抗体的能力与其诱导型抗原呈递功能直接相关。具体地说，我们现在设想了一种途径，其中吸入的抗原最初在肺中吸收，释放到循环中，在脾中回收，并且沿着激活信号，由脾树突状细胞（DC）传递到脾34 T细胞，其分化成APC。根据其自身的功能偏好，34个T细胞-APC然后调节B细胞中的T依赖性IG开关重组。本研究中的34个IgE抑制型T细胞（V34+ CD 82 +IFN-3+）降低特异性IgE抗体。我们建议测试这一假设，并通过确定抗原是否转移到IgE调节性34 T细胞，以及这些细胞是否可以作为吸入抗原的APC来研究所涉及的过程。我们还将确定吸入诱导的IgE抑制性34 T细胞是否调节抗原特异性Th 2分化，以及IFN-3是否是其调节控制中的关键介质。最后，我们将检查34个T细胞的IgE调节功能，这需要MyD 88 + DC的诱导，是否依赖于Th 1诱导这些DC产生的细胞因子，如IL-12。这些研究应该提供一个更好的理解自然的，34 T细胞介导的，控制过敏反应的机制，以及它们的潜在用途的治疗干预。 公共卫生相关性：人类对寄生虫病原体的保护部分依赖于称为IgE的抗体。不幸的是，IgE抗体也介导对称为过敏原的惰性环境物质的有害过敏反应。然而，反复吸入过敏原可以诱导耐受状态，防止以后的过敏反应。其基本机制尚未得到很好的理解。在本申请中，我们建议研究一种独特的细胞类型的作用，称为34 T细胞，其在过敏原吸入后可以防止IgE抗体的产生。我们计划的实验应该揭示这34个T细胞的调节功能是如何被诱导的，并确定它们如何发挥其调节控制作用。关于IgE调节中34种T细胞功能的新信息将有助于开发更好的方法来控制过敏性疾病中的IgE。