Role of Mast Cells in Inflammation and Immunity

肥大细胞在炎症和免疫中的作用

• 批准号: 7289692
• 负责人: Stephen Joseph Galli
• 金额: $ 39.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-20 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289692
• 关键词: 2,4-Dinitrophenol; Abbreviations; Affinity; Allergic; Antibodies; Antigens; Atopic Dermatitis; Binding; Biological; Bromodeoxyuridine; Cell physiology; Cell secretion; Cessation of life; Chymase; Complex; Contact hypersensitivity; Cutaneous; Cytoskeleton; Cytotoxic T-Lymphocytes; Dermal; Development; Dinitrofluorobenzene; Disease; Endothelin-1; Engraftment; Experimental Autoimmune Encephalomyelitis; Extracellular Matrix; Extracellular Signal Regulated Kinases; Extrinsic asthma; Fc epsilon RI; Fetal Liver; Fluorescein; Fluorescein-5-isothiocyanate; Fluoresceins; Fluorobenzenes; Funding; Glycoproteins; Haptens; Health; Health Systems Agencies; Histocytochemistry; Human; IgE; IgE Receptors; Immune response; Immunity; Immunohistochemistry; In Vitro; Individual; Inflammation; Interferons; Interleukin-10; Interleukin-2; Interleukin-3; Interleukins; Iodine-131 Human Serum Albumin; Isothiocyanates; Knock-out; Langerhans cell; Leukocytes; Leukotrienes; Ligands; Ligation; Light; Major Histocompatibility Complex; Matrix Metalloproteinases; Mediator of activation protein; Membrane; Mitogen-Activated Protein Kinases; Mitomycin; Modeling; Molecular Abnormality; Monoclonal Antibodies; Mus; Occupational; Oxazolone; Pathology; Peritoneal; Phase; Picryl Chloride; Process; Production; Proteins; Proto-Oncogene Protein c-kit; Puncture procedure; Reaction; Recombinants; Recruitment Activity; Reporting; Resolution; Role; Serum Albumin; Signal Transduction; Stem Cell Factor; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; TNFSF4 gene; Testing; Thinking; Toll-like receptors; Transforming Growth Factors; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Venous; Work; bone; cell type; cytokine; embryonic stem cell; herpesvirus entry mediator; human TNF protein; improved; in vivo; insight; mast cell; mutant; neutrophil; progenitor; progesterone 11-hemisuccinate-(2-iodohistamine); programs; repaired; response; subcutaneous; tumor necrosis factor ligand superfamily member 4

DESCRIPTION (provided by applicant): The secretion of diverse mediators & cytokines by mast cells (MCs) activated by Fc-epsilon-RI-bound IgE & specific antigen (Ag) is widely regarded to be the main process by which MCs contribute significantly to allergic disorders such as atopic dermatitis & atopic asthma. However, there is strong evidence that effector T cells also have important roles in these disorders. In other settings, including cutaneous contact hypersensitivity (CHS), T cells clearly have critical roles but the contributions of the MC have been less certain, with different studies indicating that MCs can either enhance or have no effect on individual features of CHS responses. During the last period of support, we think that we have shed light on some of the factors which may importantly influence the roles of MCs in T cell-dependent host responses & diseases, including CHS. Our findings support the general hypothesis that: 1. Depending on the circumstances, MCs can importantly contribute to the development, magnitude and, remarkably, the resolution of several features of the pathology of T cell-dependent CHS responses; and 2. MCs can have these apparently paradoxical effects by exerting both direct & indirect actions on multiple recruited or resident cell types which participate in these reactions. Specifically, we found that, depending on the specific details of hapten sensitization & challenge, MCs can either markedly enhance or significantly limit the development, extent & duration of several features of the pathology associated with CHS in the mouse. We also reported evidence that: 1. the MC's ability to influence certain biological responses, including some which are relevant to CHS, may depend on occupancy of MC Fc-epsilon-RI by Ag-non-specific IgE; and 2. MCs can enhance the proliferation & cytokine production of multiple subsets of T cells in vitro, by mechanisms which either do or do not depend on IgE+Ag signaling via Fc-epsilon-RI, MC secretion of TNF, MC-T cell proximity or MC expression of co-stimulatory molecules (e.g., OX40L). Finally, we characterized in detail a new model for investigating MC function in vivo: c-kit mutant C57QUQ-Kit h/w/sh ("W sash") mice which have been selectively "repaired" of their MC deficiency by engraftment of in vitro-derived WT MCs or MCs with defined genetic abnormalities. We now wish to capitalize on these recent insights into the complex factors which can positively or negatively regulate MC functions during immune responses by pursuing the following aims: 1: Define the mechanisms by which MCs can modulate T cell proliferation & function; 2: Define the mechanisms by which MCs can enhance the elicitation phase & the pathological consequences of cutaneous CHS responses in vivo; & 3: Define the mechanisms by which MCs can limit the magnitude & duration of CHS responses. This work promises to improve our understanding of the complex potential roles of MCs, and IgE, in health & disease, as well as to improve our understanding of the pathology of CHS, a common occupational illness.

描述（申请人提供）：被 Fc-ε-RI 结合的 IgE 和特异性抗原 (Ag) 激活的肥大细胞 (MC) 分泌多种介质和细胞因子被广泛认为是 MC 显着导致过敏性疾病（例如特应性皮炎和特应性哮喘）的主要过程。然而，有强有力的证据表明效应 T 细胞在这些疾病中也发挥着重要作用。在其他情况下，包括皮肤接触性超敏反应 (CHS)，T 细胞显然具有关键作用，但 MC 的贡献不太确定，不同的研究表明 MC 可以增强 CHS 反应的个体特征，也可以没有影响。在最后一段支持期间，我们认为我们已经阐明了一些可能对 MC 在 T 细胞依赖性宿主反应和疾病（包括中枢性低通气综合症）中的作用产生重要影响的因素。我们的研究结果支持以下一般假设： 1. 根据具体情况，MC 可以对 T 细胞依赖性 CHS 反应的病理学几个特征的发展、程度以及显着的解决做出重要贡献； 2. MC 通过对参与这些反应的多种募集或常驻细胞类型施加直接和间接作用，可以产生这些明显矛盾的效应。具体来说，我们发现，根据半抗原致敏和攻击的具体细节，MC 可以显着增强或显着限制小鼠中与 CHS 相关的几种病理特征的发展、程度和持续时间。我们还报告了以下证据： 1. MC 影响某些生物反应的能力，包括一些与 CHS 相关的生物反应，可能取决于 Ag-非特异性 IgE 对 MC Fc-ε-RI 的占据； 2. MC 可以通过依赖或不依赖于 Fc-epsilon-RI 的 IgE+Ag 信号转导、TNF 的 MC 分泌、MC-T 细胞邻近性或共刺激分子（例如 OX40L）的 MC 表达的机制，在体外增强多个 T 细胞亚群的增殖和细胞因子产生。最后，我们详细描述了一种用于研究体内 MC 功能的新模型：c-kit 突变型 C57QUQ-Kit h/w/sh（“W sash”）小鼠，通过植入体外衍生的 WT MC 或具有明确遗传异常的 MC，选择性“修复”其 MC 缺陷。我们现在希望利用这些最新的见解，通过追求以下目标，在免疫反应过程中积极或消极地调节 MC 功能的复杂因素： 1：定义 MC 调节 T 细胞增殖和功能的机制； 2：定义 MC 增强诱发阶段的机制以及体内皮肤 CHS 反应的病理后果； & 3：定义 MC 可以限制 CHS 响应的幅度和持续时间的机制。这项工作有望提高我们对 MC 和 IgE 在健康和疾病中复杂的潜在作用的理解，并提高我们对常见职业病中枢性低通气综合症 (CHS) 病理学的理解。