Role of Mast Cells in Inflammation and Immunity

描述（由申请人提供）：由Fc-γ-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显著促进过敏性疾病（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具有重要作用。在其他环境中，包括皮肤接触超敏反应（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可以增强或对CHS反应的个体特征没有影响。在上一个支持期间，我们认为我们已经阐明了一些可能重要影响MC在T细胞依赖性宿主反应和疾病（包括CHS）中作用的因素。我们的研究结果支持一般假设，即：1。根据情况，MC可以重要地促进T细胞依赖性CHS应答的病理学的几个特征的发展、幅度和显著的分辨率;和2. MC可以通过对参与这些反应的多种募集或驻留细胞类型施加直接和间接作用来产生这些明显矛盾的效应。具体而言，我们发现，根据半抗原致敏和激发的具体细节，MC可以显著增强或显著限制小鼠中与CHS相关的病理学的几个特征的发展、程度和持续时间。我们还报告了证据表明：1。MC影响某些生物学应答的能力，包括一些与CHS相关的生物学应答，可能取决于Ag-非特异性IgE对MC Fc-γ-RI的占据;和2. MC可以通过依赖于或不依赖于经由Fc-γ-RI的IgE+Ag信号传导、MC分泌TNF、MC-T细胞接近或MC表达共刺激分子（例如，0X40L）。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C57 QUQ-Kit h/w/sh（“W sash”）小鼠，其通过移植体外衍生的WT MC或具有确定的遗传异常的MC来选择性地“修复”其MC缺陷。我们现在希望通过追求以下目标来利用这些对在免疫应答期间可以积极或消极调节MC功能的复杂因素的最新见解：1：定义MC可以调节T细胞增殖和功能的机制; 2：定义MC可以增强体内皮肤CHS应答的激发阶段和病理后果的机制; 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潜在作用的理解，并提高我们对CHS（一种常见职业病）病理学的理解。

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.