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

供受者之间的HL A相容是器官移植成功的关键因素。预制的人类白细胞抗原抗体可导致急性排斥反应，器官移植后新形成的抗体可降低器官功能和成功率。人类白细胞抗原的亲和性取决于人类白细胞抗原的基因分型，而人类白细胞抗原分子的免疫原性取决于其三维结构。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，对体外受精计划中反复发生胚胎植入失败的夫妇进行了淋巴细胞免疫治疗。女性用伴侣的外周血淋巴细胞进行皮内免疫。4周后，血清中可检测到抗人类白细胞抗原抗体，可作为免疫的替代标志。因此，我们已经获得了世界范围内唯一的血清队列，这些血清来自同种异体免疫前后的健康个体，并处于确切的已知的人类白细胞抗原环境中。与器官移植相比，不受免疫抑制药物的影响，因此我们可以根据免疫妇女的人类白细胞抗原背景确定单个人类白细胞抗原等位基因的免疫原性。在之前的一项研究中，我们向我们的合作伙伴Kosmoliaptsis博士(剑桥)提供了191对LIT夫妇的人类白细胞抗原分型和人类白细胞抗原抗体结果，他开发了剑桥人类白细胞抗原免疫原性算法，该算法基于主要是白种人的人类白细胞抗原表型。在目前应用的项目框架内，我们希望从我们的文学队列中再包括100对夫妇，其中至少有一对(或两对)不是德国人、波兰人、斯堪的纳维亚人或俄罗斯人的后裔。有照明前和照明后以及DNA可供选择。双方都将是HLA型(高分辨率)，点燃前和点燃后血清中的抗体将通过Luminex技术进行分析和指定。结果将被传送给Kosmoliaptsis博士，以整合到剑桥人类白细胞抗原免疫原性算法中。我们预计，包含频率较低的HLA等位基因将使该算法更加适用。总体而言，长期目标是将剑桥人类白细胞抗原免疫原性算法纳入国家和国际器官分配系统(欧洲移植)。

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).