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

受体与供体之间的HLA相容性是器官移植成功的关键因素。预先形成的HLA抗体可诱导急性排斥反应，器官移植后新形成的抗体可降低器官功能和成功率。HLA相容性由HLA基因分型决定，但HLA分子的免疫原性由其三维结构决定。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，对体外受精程序中反复胚胎植入失败的夫妇进行淋巴细胞免疫疗法（LIT）。该妇女是免疫接种与合作伙伴的外周血淋巴细胞皮内。4周后，血清中可检测到抗HLA抗体，作为免疫的替代标志物。因此，我们有一个世界范围内独特的血清队列，从其他健康的个人之前和之后，同种异体免疫，并在一个精确的已知的HLA设置。与器官移植相反，没有免疫抑制药物的影响，因此我们可以根据免疫妇女的HLA背景确定单个HLA等位基因的免疫原性。在之前的研究中，我们向我们的合作伙伴Kosmoliaptsis博士（剑桥）提供了191对LIT夫妇的HLA分型和HLA抗体结果，Kosmoliaptsis博士基于大多数高加索人群的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内，我们希望从我们的LIT队列中再纳入100对夫妇，其中至少一对（或两对）不是德国，波兰，斯堪的纳维亚或俄罗斯血统。前和后LIT以及DNA是可用的。将对两个伴侣进行HLA分型（高分辨率），并通过Luminex技术分析和指定LIT前后血清中的抗体。将结果转移至Dr. Kosmoliaptsis，以整合至剑桥HLA免疫原性算法中。我们预计，包括不太频繁的HLA等位基因将使算法更适合。总体而言，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（Eurotransplant）。

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).