Role of Mast Cells in Inflammation and Immunity

描述(由申请人提供)：由Fc-epsilon-RI结合的IgE和特异性抗原(Ag)激活的肥大细胞(MCs)分泌不同的介质和细胞因子被广泛认为是MCs导致过敏性疾病(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，效应性T细胞在这些疾病中也扮演着重要的角色。在其他环境中，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的作用一直不太确定，不同的研究表明MC可以增强CHS反应的个体特征，也可以对CHS的个体特征没有影响。在最后的支持期间，我们认为我们已经阐明了一些因素，这些因素可能对MC在T细胞依赖性宿主反应和疾病(包括CHS)中的作用产生重要影响。我们的发现支持这样一个普遍的假设：1.根据不同的情况，MC可以对T细胞依赖的CHS反应的一些病理特征的发展、大小和显著的解决做出重要贡献；以及2.MC可以通过对参与这些反应的多种招募或驻留的细胞类型施加直接和间接作用而具有这些明显的矛盾效应。具体地说，我们发现，根据半抗原敏化和挑战的具体细节，MC可以显著增强或显著限制与CHS相关的几个病理特征的发展、程度和持续时间。我们还报道了以下证据：1.MC影响某些生物学反应的能力，包括一些与CHS相关的反应，可能依赖于非特异性IgE对MC Fc-epsilon-RI的占据；以及2.MCS在体外可以促进多个T细胞亚群的增殖和细胞因子的产生，其机制是通过Fc-epsilon-RI、MC分泌肿瘤坏死因子、MC-T细胞接近或MC表达共刺激分子(如OX40L)来实现或不依赖于IgE+Ag信号。最后，我们详细描述了一个研究MC体内功能的新模型：C-KIT突变体C57QUQ-Kit h/w/sh(“W sash”)小鼠，它们通过植入体外来源的WT MC或具有明确遗传异常的MC而选择性地“修复”了它们的MC缺陷。我们现在希望利用这些最新的见解，通过追求以下目标来研究在免疫反应过程中可以积极或消极地调节MC功能的复杂因素：1：确定MC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反应的诱导期和病理后果的机制；3：定义MC可以限制CHS反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在健康和疾病中的复杂潜在作用的理解，以及提高我们对CHS这一常见职业病的病理学的理解。

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.