Exploring, Understanding and Intervening in IgE-dependent Mechanisms in Allergic Disease and Asthma

探索、理解和干预过敏性疾病和哮喘的 IgE 依赖性机制

• 批准号: G0501494/1
• 负责人: Brian Sutton
• 金额: $ 292.37万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501494%2F1
• 关键词: Exploring; Understanding; Intervening; IgE; dependent

The incidence of allergic disease, and asthma in particular, has increased alarmingly in the UK and there is an urgent need for new therapies. Antibodies of a type known as immunoglobulin E (IgE) are crucially involved in the allergic response, and individuals susceptible to allergies have high IgE levels. These IgE antibodies recognise allergens that enter the airways (e.g. grass pollen), the gut (food allergens) or the skin (contact allergies), and then trigger allergic reactions. We know, from the success of an anti-IgE treatment, that removal of IgE relieves allergic symptoms. But anti-IgE, itself an antibody, is very expensive, requires administration in the clinic, and is licensed only for severe asthma. By understanding how the body produces IgE, and the way IgE activates allergic reactions, we expect to discover new ways to inhibit IgE, and develop compounds that are cheaper, more widely applicable to different allergic conditions, and easier to administer. The cells in the body that make antibodies, B-cells, switch in response to certain signals from producing beneficial, protective antibodies to producing IgE; our aim is to understand and prevent this switch. We have discovered that switching can occur in the nose rather than, as previously thought, only in lymph nodes, and now, using nasal tissue available from a surgical procedure (to clear nasal passages) developed at Guy?s Hospital, we can study the process in detail. We shall use an ultra-high resolution microscope (the first of its kind in the UK) to study events within the B-cell nucleus as the genes for IgE are switched on, and then study the survival and proliferation of these IgE-producing cells. This work will undoubtedly identify new targets for intervention.We have also discovered that ?superantigens?, bacterial molecules that trigger antibody production, are present in asthmatic patients? airways. We believe that these superantigens may promote IgE production, in the lung or nose, and will study how they interact with IgE ? opening up a new approach to allergy treatment. We will also investigate the claim that certain IgE molecules are more active than others in triggering allergy. We have already determined the molecular structure of IgE and found that it changes its shape when it triggers an allergic reaction. We can now test compounds that prevent this change in shape, collaborating with the pharmaceutical industry to develop small-molecule inhibitors that overcome the limitations of anti-IgE.

在英国，过敏性疾病，特别是哮喘的发病率惊人地增加，迫切需要新的治疗方法。一种称为免疫球蛋白E（IgE）的抗体在过敏反应中起着至关重要的作用，对过敏敏感的个体具有高IgE水平。这些IgE抗体识别进入气道（例如草花粉），肠道（食物过敏原）或皮肤（接触性过敏）的过敏原，然后引发过敏反应。我们知道，从抗IgE治疗的成功，IgE的去除缓解过敏症状。但抗IgE抗体本身是一种抗体，非常昂贵，需要在诊所使用，并且只被许可用于严重的哮喘。通过了解身体如何产生IgE，以及IgE激活过敏反应的方式，我们希望发现抑制IgE的新方法，并开发更便宜，更广泛适用于不同过敏状况，更容易管理的化合物。身体中产生抗体的细胞，B细胞，会对某些信号做出反应，从产生有益的保护性抗体转变为产生IgE;我们的目标是了解和防止这种转变。我们已经发现，转换可以发生在鼻子，而不是像以前认为的那样，只在淋巴结，现在，使用鼻组织可从外科手术（清理鼻腔通道）开发的盖伊？我们可以详细研究这个过程。我们将使用超高分辨率显微镜（英国首个此类显微镜）研究B细胞核内IgE基因启动时的事件，然后研究这些产生IgE的细胞的存活和增殖。这项工作无疑将确定新的干预目标。我们还发现，？超级抗原？引发抗体产生的细菌分子，存在于哮喘患者体内？航空公司.我们相信，这些超抗原可能会促进IgE的产生，在肺或鼻子，并将研究它们如何与IgE相互作用？开辟了一种治疗过敏症的新方法。我们还将研究某些IgE分子在引发过敏方面比其他分子更活跃的说法。我们已经确定了IgE的分子结构，发现当它引发过敏反应时，它会改变形状。我们现在可以测试阻止这种形状变化的化合物，与制药行业合作开发克服抗IgE局限性的小分子抑制剂。