Lymphocyte immunotherapy (LIT) as a model system to predict humoral alloimmunity in transplantation: Validation of the Cambridge HLA immunogenicity algorithm

淋巴细胞免疫疗法 (LIT) 作为预测移植中体液同种免疫的模型系统：剑桥 HLA 免疫原性算法的验证

• 批准号: 335741949
• 负责人: Professor Dr. Dietrich Kabelitz
• 金额: --
• 依托单位: Institut für Immunologie
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/335741949?language=en
• 关键词: Lymphocyte; immunotherapy; LIT; model; system

HLA compatibility between recipient and donor is a key factor for success in organ transplantation. Preformed HLA antibodies can induce acute rejection, and newly formed antibodies after organ transplantation can reduce organ function and success rates. HLA compatibility is determined by HLA genotyping, but immunogenicity of HLA molecules is determined by their three-dimensional structure. Since more than 20 years, lymphocyte immunotherapy (LIT) is performed at the Institute of Immunology, Kiel University, in couples suffering from recurrent embryo implantation failure in in-vitro fertilization programmes, after careful exclusion of all other possible factors. The woman is immunized intradermally with partners peripheral blood lymphocytes. After 4 weeks, anti-HLA antibodies are detectable in the serum as a surrogate marker of immunization. We have thus available a worldwide unique cohort of sera from otherwise healthy individuals before and after allo-immunization and in a precisely known HLA setting. In contrast to organ transplantation, there is no influence of immunosuppressive medication, and we can thus determine the immunogenicity of individual HLA alleles against the HLA background of the immunized woman. In a previous study we provided HLA typing and HLA-antibody results from 191 LIT couples to our collaboration partner Dr. Kosmoliaptsis (Cambridge) who has developed the Cambridge HLA immunogenicity algorithm based on the HLA phenotypes of mostly causasian population. In the frame of the currently applied project we would like to include 100 more couples from our LIT cohort, of which at least one (or both) are not of German, Polnish, Scandinavian or Russian descent. Pre- and post-LIT as well as DNA is available. Both partners will be HLA typed (high resolution), and antibodies in pre- and post-LIT sera will be analyzed and specified by Luminex technology. Results will be transferred to Dr. Kosmoliaptsis for integration into the Cambridge HLA immunogenicity algorithm. We anticipate that the inclusion of less frequent HLA alleles will make the algorithm even more suitable. Overall, the long-term goal is to include the Cambridge HLA immunogenicity algorithm into national and international organ allocation systems (Eurotransplant).

受体和供体之间的HLA相容性是器官移植成功的关键因素。预先形成的HLA抗体可诱发急性排斥反应，器官移植后新形成的抗体可降低器官功能和成功率。HLA相容性是由HLA基因分型决定的，而HLA分子的免疫原性是由它们的三维结构决定的。20多年来，基尔大学免疫学研究所在仔细排除所有其他可能因素后，对体外受精方案中反复发生胚胎植入失败的夫妇进行淋巴细胞免疫治疗（LIT）。妇女用伴侣外周血淋巴细胞进行皮内免疫。4周后，血清中可检测到hla抗体作为免疫的替代标志物。因此，我们获得了一个世界范围内独一无二的健康个体在同种异体免疫前后以及在精确已知的HLA设置下的血清队列。与器官移植相比，免疫抑制药物没有影响，因此我们可以根据免疫妇女的HLA背景来确定个体HLA等位基因的免疫原性。在之前的一项研究中，我们将191对LIT夫妇的HLA分型和HLA抗体结果提供给了我们的合作伙伴Kosmoliaptsis博士（剑桥），他基于大多数致病人群的HLA表型开发了剑桥HLA免疫原性算法。在目前申请的项目框架中，我们希望从我们的LIT队列中再纳入100对夫妇，其中至少有一对（或两对）不是德国、波兰、斯堪的纳维亚或俄罗斯血统。Pre和post-LIT以及DNA都是可用的。双方都将是HLA型（高分辨率），并且将使用Luminex技术分析和指定lit前后血清中的抗体。结果将转交给Kosmoliaptsis博士，以整合到剑桥HLA免疫原性算法中。我们预计，包含较少频率的HLA等位基因将使该算法更加适用。总的来说，长期目标是将剑桥HLA免疫原性算法纳入国家和国际器官分配系统（欧洲移植）。