Inhalation Tolerance, IgE and gamma/delta T cells

吸入耐受性、IgE 和 γ/δ T 细胞

• 批准号: 8422967
• 负责人: WILLI K BORN
• 金额: $ 19.81万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422967
• 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.

描述(由申请人提供)：通过接触粘膜抗原产生的免疫耐受是过敏原特异的、高效和持久的。尽管这些特点应该使其适合于免疫疾病的治疗，但目前的特异性免疫治疗方案很少利用它。更好地了解这些机制可能会简化治疗，并有助于避免潜在的危险暴露。已知粘膜对吸入性抗原的耐受可由34T细胞介导。在小鼠的细胞转移实验中，反复抗原吸入耐受的供者的脾34T细胞被证明以惊人的高效率抑制对该抗原的IgE反应，同时保持免疫球蛋白水平不变。虽然34T细胞通常不是由常规抗原选择的，但对IgE的抑制似乎是抗原特异性的，但其潜在的机制尚不清楚。我们已经确定了脾中IgE抑制的34T细胞的特征，我们的初步数据现在为它们的抗原特异性提供了直接的支持。此外，我们的新数据表明，这34个T细胞是由脾树突状细胞(DC)诱导的，并且自身具有抗原提呈细胞(APC)的功能，从而阻止T辅助2(Th2)细胞的发展。我们假设，34个T细胞调节T依赖的特异性IgE抗体的能力与其可诱导的抗原提呈功能直接相关。具体地说，我们现在设想了一种途径，即最初在肺中吸收的吸入抗原被释放到循环中，在脾中回收，并与激活信号一起由脾树突状细胞(DC)传递给脾34 T细胞，后者分化为APC。在自身功能偏向的支配下，34个T细胞-APC调节B细胞中T依赖的Ig开关重组。本研究中的34个IgE抑制型T细胞(V34+CD82+干扰素-3+)可降低特异性IgE抗体。我们建议验证这一假设，并通过确定抗原是否转移到IgE调节34T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34T细胞是否调节抗原特异性Th2的分化，以及干扰素-3是否在它们的调控中起关键的中介作用。最后，我们将研究需要MyD88+DC诱导的34个T细胞的IgE调节功能是否依赖于这些DC产生的Th1诱导细胞因子，如IL-12。这些研究应该能更好地理解自然的、34T细胞介导的过敏反应的控制机制，以及它们在治疗干预中的潜在用途。