Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells

生物学家已经给几乎所有不同的蛋白质分子起了名字，这些蛋白质分子调节着人类细胞之间的通讯。现在，当代细胞生物学的大胆目标是了解活细胞中的10亿种蛋白质如何允许它们移动、繁殖、对大脑做出贡献或保护我们免受病毒和细菌的伤害。在这一前沿领域，成像技术在蛋白质相互作用的地点和时间发挥着重要作用。最近对几种蛋白质的成像已经在免疫细胞如何相互沟通以及如何识别疾病征兆方面产生了重要的新概念。免疫细胞与其他细胞接触的高分辨率显微镜图像显示了临时的膜结构，通常被称为免疫突触，类似于神经细胞为了交流而相互制造的突触。蛋白质通常在细胞之间的接触处分离到特定的区域，探索这种蛋白质变化的排列是如何发生的，以及它们如何控制免疫细胞的交流，这是免疫突触概念开启的一门新科学。在过去的十年中，抗体的使用彻底改变了人类严重疾病的治疗，如非霍奇金淋巴瘤(NHL)和类风湿性关节炎(RA)。这些抗体的一种工作方式是通过触发自然杀伤细胞直接杀死患病的目标细胞。至关重要的是，还没有人确定当抗体触发对患病细胞的杀死时，免疫突触会发生什么。在这里，我们计划使用最先进的技术来对抗体介导的杀戮过程中的免疫突触进行成像，以期了解如何最好地优化抗体以实现这一功能。我们将把从这些基础研究中获得的理解应用于合理设计修饰抗体，以在一系列疾病治疗中实现最佳效率。

Biologists have given names to nearly all the different protein molecules that mediate communication between human cells. Now, the audacious goal of contemporary cell biology is to understand how the billion proteins in a live cell allow them to move, multiply, contribute to a brain or defend us against viruses and bacteria. Imaging where and when proteins interact with each other has a major role to play at this frontier. Recent imaging of just a few types of proteins has already led to important new concepts in how immune cells communicate with each other and how they recognize signs of disease. High-resolution microscope images of immune cells contacting other cells have revealed temporary membrane structures, often called immune synapses, similar to the synapses that nerve cells make with one another for communication. Proteins commonly segregate into specific regions at the contacts between cells, and exploring how such changing arrangements of proteins occur and how they control immune cell communication is the new science opened up by the immune synapse concept. Over the last decade the use of antibodies has revolutionised the treatment of severe human diseases, such as non hodgkins lymphoma (NHL) and rheumatoid arthritis (RA). One way that these antibodies work is by triggering Natural Killer cells to directly kill diseased target cells. Crucially, nobody has yet determined what happens at immune synapses when antibodies trigger killing of diseased cells. Here, we plan to use state-of-the-art technologies to image immune synapses during antibody-medaited killing with a view to learning how to best optimise antibodies for this function. We will apply the understanding gained from these basic studies to the rational design of modified antibodies for optimal efficiency in a range of disease treatments.