ADCC · Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-09-01 → 2013-02-28
- Финансиране от ЕС
- 37 500 €
- Участници
- 1
- Схема
- MC-ERG
Линиите свързват координатора с партньорите.
Накратко на български
Механизмите, по които NK клетките унищожават болни B клетки чрез антителото ритуксимаб, се проучват с помощта на микроскопия. Разбирането на тези процеси на клетно ниво помага за оптимизирането на антителата при лечение на рак и автоимунни заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells
In the last 15 years the use of drugs called monoclonal antibodies has revolutionised the treatment of severe human diseases including cancers and autoimmune conditions. What is still not completely understood is why some drugs are much more efficient at eradicating diseased cells than others. Therefore it is important to understand the exact mechanisms of action of these successful drugs to identify what makes them so effective. Rituximab is a potent monoclonal antibody mediating depletion of B cells. One way by which it exerts its function is by triggering Natural Killer (NK) cells to directly kill diseased B cells coated with rituximab. Despite a high importance of the process of antibody-mediated killing in mediating efficient immune response to diseased B cells in patients not much is known about the process itself and more research was required to study what happens during antibody-mediated killing on the single cell level with a view to learning how to best optimise antibodies for this function. Therefore we sought to investigate the string of events leading from the initial coating of B cell with rituximab to the eventual killing by NK cell. Using the state of the art microscopy techniques we studied the behaviour of human B and NK cells when co-cultured in the presence of rituximab. We showed that binding of rituximab to B cell induces changes within the cell that may then be important for the outcome of the interaction with effector NK cell. Rituximab induced modifications in the localisation of CD20 - its target protein - on the B cell surface leading to its polarisation on one side of the cell. Importantly this was specific to rituximab as another antibody targeting a similar epitope within CD20 on B cells did not induce the same type of modifications. Importantly the process of CD20 polarisation was not a mere clustering of antigen by the antibody as other proteins such as ICAM-1 and moesin co-localised with CD20 in the same place indicating that rituximab caused a polarisation of B cells. This process of polarisation was then important for target cell killing as the cells with evident CD20 clustering were killed more efficiently by NK cells than those with homogenous distribution of the protein. This highlights a new aspect of rituximab involvement in mediating efficient ADCC. The polarisation of B cells induced by rituximab augments its therapeutic role in triggering ADCC by effector NK cells. Many factors must be considered in the rational design of antibodies for use in ADCC and here we describe one possibly important factor that could be taken into account that involves changes to the cell surface organisation of the target cell. It may be important to consider screening potential therapeutic antibodies for their ability to trigger modification in target antigen organisation and cellular polarisation.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
High-resolution microscope images of immune cells contacting other cells have revealed temporary membrane structures, often called immune synapses (IS). 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 monoclonal 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. Typically antibodies have been used to either block ligand receptor interactions or to evoke antibody effector function and kill malignant target cells by antibody-dependent cell cytotoxicity (ADCC). Crucially, nobody has yet determined what happens at IS when antibodies trigger killing of diseased cells. Through this project we will focus our research to improve our basic understanding of the molecular dynamics that occur during ADCC and to investigate antibodies specifically engineered to enhance ADCC. Here, we plan to use state-of-the-art technologies to image IS during antibody-mediated killing with a view to learning how to best optimize antibodies for this function. Specifically, the spatial relationship and segregation of proteins at the submicrometer scale will be determined during ADCC and compared for the different antibodies and model systems developed. This will establish what determines the efficiency of ADCC and will facilitate the rational design of modified antibodies for optimal medical use. This project will benefit from the knowledge and experience in imaging and cell biology techniques gained by the researcher during her initial training. It will also provide the researcher with invaluable new experience adding to her career development.
Оригинален текст от CORDIS (на английски).
Участници
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз