FLT3-LIGAND, IMMUNOMODULATION AND THERAPY IN ASTHMA

FLT3-配体、免疫调节和哮喘治疗

• 批准号: 7608532
• 负责人: Devendra K. Agrawal
• 金额: $ 2.3万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608532
• 关键词: Acute; Adoptive Transfer; Allergens; Allergic; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Appendix; Asthma; Biological Assay; Breathing; CD8B1 gene; Cells; Chronic; Clinic; Clinical; Coculture Techniques; Cryoultramicrotomy; Data; Dendritic Cells; Disease; Dose; Eosinophilia; Event; FLT3 ligand; Frequencies; Future; Goals; Growth Factor; Hematopoietic; Histopathology; IL12B gene; Immune; Immune response; Immunity; Immunohistochemistry; Inflammation; Interferons; Interleukin-10; Interleukin-12; Knock-out; Knockout Mice; Ligands; Liquid substance; Lung; Lung diseases; Lymphocyte; Mediating; Modeling; Mus; Numbers; Ovalbumin; Pathogenesis; Phenotype; Population; Principal Investigator; Process; Production; Regulation; Reporting; Serological; Serum; Specificity; Spleen; Stem cells; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Time; Translating; airway hyperresponsiveness; allergic airway inflammation; asthmatic patient; base; collagenase; cytokine; egg; environmental allergen; immune function; immunoregulation; loss of function; lymph nodes; macrophage; mouse model; neutralizing antibody; prevent; progenitor; programs; prophylactic; pulmonary function; response; sensitizing antigen; spatial relationship

Fit-3 Ligand (FL) is a growth factor for DCs, and induces a type 1 T cell response. We recently reported that FL prevented ovalbumin-induced allergic airway inflammation in mice and suppressed late allergic response (LAR) and airway hyperresponsiveness (AHR). Based on these studies we developed the hypothesis that FL has therapeutic activity for asthma via cellular immunoregulatory mechanism that are allergen non-specific. In Specific Aim 1, we will examine the ability of FL to reverse LAR, AHR and eosinophilia in a mouse model of allergic airway inflammation and augment an antigen-specific, type 1 T cell response to the inciting allergen. We will determine the dose-response for FL therapeutic activity and duration of effect. We will also examine the effect of FL on clinical correlates of asthma including baseline AHR in mice sensitized, but not challenged with the allergen. Further we will examine the levels and isotype of antibodies to the allergen and cytokine levels in serum and lung washings, in addition to non-antigen and antigen-specific type 1 and 2 T cell responses by Elispot assays both systemically (spleen) and regionally (lymph nodes and collagenase digested lungs). In Specific Aim 2, we will determine whether FL therapeutic activity in acute and chronic asthma is due to IL-12 regulation of a type 1 immune response. We will determine the therapeutic activity of FL in wild type and IL-12b knock-out (KO) mice, and also examine the therapeutic activity of FL in animals given neutralizing antibodies to IL-12 during allergic airway inflammation. The immune function studies will focus on both DC and T-cells from draining lymph nodes and lungs to examine the underlying mechanisms of FL-induced regulation of type 2 cytokine responses. In Specific Aim 3, we will determine whether FL therapeutic activity in acute and chronic asthma is due to tolerance induction via expansion of immature DCs and/or CD4+-CD25+ regulatory T cells (Tr cells). Further, using cellular adoptive transfer studies we will identify the ability of DCs and Tr cells from naive and antigen-sensitized mice treated with FL to protect against and also treat antigen-specific asthma. We will also examine the histopathology of asthma and spatial relationship with immune cells and examine the production of type 1 and 2 cytokines. The long-term goal of this study is to better define the potential mechanisms of action of FL to prevent and reverse allergic airway inflammation and associated changes in pulmonary function.

FIT-3配体（FL）是DC的生长因子，并诱导1型T细胞反应。我们最近报道了 FL防止小鼠椭圆形诱导的过敏性气道炎症并抑制晚期过敏反应 （LAR）和气道高反应性（AHR）。基于这些研究，我们提出了一个假设，即 通过过敏原非特异性的细胞免疫调节机制具有治疗活性。 在特定的目标1中，我们将检查小鼠模型中FL逆转LAR，AHR和嗜酸性的能力 过敏性气道炎症和增强抗原特异性的1型T细胞对煽动的反应 过敏原。我们将确定FL治疗活性和效果持续时间的剂量反应。我们也会 检查FL对哮喘的临床相关性的影响，包括小鼠的基线AHR，但却不 受到过敏原挑战。此外，我们将研究过敏原抗体的水平和同型 除非非抗原和抗原特异性1和2 T外，血清和肺洗涤的细胞因子水平 ELISPOT测定的细胞反应是系统地（脾脏）和区域性的（淋巴结和胶原酶 消化的肺）。在特定的目标2中，我们将确定急性和慢性的FL治疗活性是否 哮喘是由于IL-12对1型免疫反应的调节。我们将确定 野生型和IL-12b敲除（KO）小鼠的FL，还检查动物中FL的治疗活性 在过敏性气道炎症期间给予对IL-12的中和抗体。免疫功能研究将 专注于排水淋巴结和肺的直流和T细胞，以检查的基本机制 FL诱导的2型细胞因子反应的调节。在特定目标3中，我们将确定是否fl 急性和慢性哮喘的治疗活性是由于未成熟DC的扩张而耐受性诱导的 和/或CD4+ -CD25+调节T细胞（TR细胞）。此外，使用蜂窝收养转移研究我们将 确定从幼稚和抗原敏感的小鼠用FL处理以保护的DC和TR细胞的能力 反对并治疗抗原特异性哮喘。我们还将检查哮喘和 与免疫细胞的空间关系并检查1型和2个细胞因子的产生。长期 这项研究的目标是更好地定义FL的潜在作用机理，以预防和逆转过敏 气道炎症和肺功能的相关变化。

项目成果

The impact of vitamin D on asthmatic human airway smooth muscle.

• DOI: 10.1586/17476348.2016.1128326
• 发表时间: 2016-02
• 期刊: Expert review of respiratory medicine
• 影响因子: 3.9
• 作者: Hall SC;Fischer KD;Agrawal DK
• 通讯作者: Agrawal DK

Fms-like tyrosine kinase 3 ligand increases a lung DC subset with regulatory properties in allergic airway inflammation.

• DOI: 10.1016/j.jaci.2009.01.052
• 发表时间: 2009-04
• 期刊: The Journal of allergy and clinical immunology
• 作者: Z. Shao;A. Bharadwaj;H. McGee;T. Makinde;D. Agrawal

Intra and extravascular transmembrane signalling of angiopoietin-1-Tie2 receptor in health and disease.

• DOI: 10.1111/j.1582-4934.2008.00254.x
• 发表时间: 2008-06
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Makinde T;Agrawal DK
• 通讯作者: Agrawal DK

Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation.

• DOI: 10.1586/17476348.2016.1133303
• 发表时间: 2016-02
• 期刊: Expert review of respiratory medicine
• 影响因子: 3.9
• 作者: Hall SC;Agrawal DK
• 通讯作者: Agrawal DK

Temporal PTEN inactivation causes proliferation of saphenous vein smooth muscle cells of human CABG conduits.

• DOI: 10.1111/j.1582-4934.2008.00311.x
• 发表时间: 2009-01
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Mitra AK;Jia G;Gangahar DM;Agrawal DK
• 通讯作者: Agrawal DK