权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Repertoire and antigen recognition of brain-infiltrating immune cells in progressive MS

进行性多发性硬化症脑浸润免疫细胞的库和抗原识别

基本信息

批准号：
340260765
负责人：
Privatdozent Dr. Klaus Dornmair
金额：
--
依托单位：
Abteilung Neuroimmunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/340260765?language=en
关键词：
Repertoire antigen recognition brain infiltrating

项目摘要

Cells from the immune system (lymphocytes, for example T cells and B cells/plasma cells) are found in the brains of patients with multiple sclerosis (MS), located in areas where myelin sheaths are destroyed and where neurons degenerate. Moreover, these cells are found in MS brains at the very beginning of the disease, in the relapsing-remitting stage, and also in the progressive phase of the disease. Do these cells belong just to a few clones gone awry, or to many different ones?What do they recognize?Do immune cells found in the brain of very early MS recognize the same antigens as immune cells found later, in the progressive phase of the disease?Studies to find answers for these questions have not been done yet for patients with progressive MS where suitable material is extremely rare and often formaldehyde-fixed and paraffin-embedded (FFPE) deemed useless for further analysis. However, we have such precious samples, and we have the expertise to use FFPE tissue for molecular studies. Studies of pathogenic lymphocytes within the tissue require sophisticated techniques like next generation sequencing to learn more about their repertoire (which is, to learn how different their antibodies and T cell receptors are, and whether they belong to few or many different clones). Over the last years, also these techniques have been adjusted to FFPE samples. Disease-relevant cells are typically expanded within the tissue. Therefore, we will next clone and express the most abundant antibodies and T cell receptors identified in the progressive MS brains to find out what these molecules recognize. And finally, when we know this, we will go back to pathology to find out when and where this recognition occurs. Answers to these questions could help to better understand the driving forces of MS, and perhaps even to find better therapies for MS.It can be easily envisaged that such a demanding and important project will only be successful when specialists for all these steps jointly work together. In our case, the technical know-how needed to achieve this goal is complementarily distributed between two groups, on of them located in Vienna, Austria (Monika Bradl and Hans Lassmann), the other one located in Munich, Germany (Klaus Dornmair). Therefore, we propose a joint binational project of our two groups under the DACH lead agency action. Such a joint project has an especially important point of added value since we will be able to directly compare our data and antigens from progressive MS to those obtained from samples with relapsing remitting MS and with very early MS (data currently obtained in a project supported by DFG, proposal CRC TR 128 A5).

来自免疫系统的细胞（淋巴细胞，例如T细胞和B细胞/浆细胞）存在于多发性硬化症（MS）患者的脑中，位于髓鞘被破坏和神经元退化的区域。此外，这些细胞在疾病开始时，在复发-缓解阶段以及疾病的进展阶段发现于MS脑中。这些细胞是属于几个出了问题的克隆体，还是属于许多不同的克隆体？他们认识什么？在早期MS的大脑中发现的免疫细胞是否与后来在疾病的进展阶段发现的免疫细胞识别相同的抗原？尚未对进展性MS患者进行研究以寻找这些问题的答案，其中合适的材料极其罕见，并且通常被认为对进一步分析无用。然而，我们有如此珍贵的样本，我们有专业知识使用FFPE组织进行分子研究。对组织内致病淋巴细胞的研究需要复杂的技术，如下一代测序，以了解更多关于它们的库（即了解它们的抗体和T细胞受体的差异，以及它们是否属于少数或许多不同的克隆）。在过去的几年里，这些技术也已调整到FFPE样品。疾病相关细胞通常在组织内扩增。因此，我们接下来将克隆并表达在进行性MS大脑中鉴定的最丰富的抗体和T细胞受体，以找出这些分子识别的是什么。最后，当我们知道这一点时，我们将回到病理学来找出这种识别发生的时间和地点。这些问题的答案可能有助于更好地理解MS的驱动力，甚至可能找到更好的MS疗法。可以很容易地想象，只有当所有这些步骤的专家共同努力时，这样一个要求苛刻和重要的项目才会成功。在我们的情况下，实现这一目标所需的技术诀窍在两个小组之间互补分配，其中一个小组位于奥地利的维也纳（Monika Bradl和Hans Lassmann），另一个小组位于德国的慕尼黑（Klaus Dornmair）。因此，我们建议在DACH牵头机构的行动下，由我们两个团体联合开展一个两国项目。这样的联合项目具有特别重要的附加值，因为我们将能够直接比较我们从进行性MS获得的数据和抗原与从复发缓解型MS和极早期MS样本获得的数据和抗原（目前在DFG支持的项目中获得的数据，提案CRC TR 128 A5）。