The immunogenicity and pathogenicity of HLA-DQ in solid organ transplantation

HLA-DQ在实体器官移植中的免疫原性和致病性

• 批准号: 10658665
• 负责人: Anat R. Tambur
• 金额: $ 80万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658665
• 关键词: Address; Adsorption; Affect; Algorithms; Alleles; Allografting; Amino Acids; Antibodies; Antibody Formation; Antigen Presentation Pathway; Applied Research; B-Lymphocytes; CRISPR/Cas technology; Categories; Cell Line; Cell surface; Cells; Characteristics; Color; Computer software; Development; Endothelial Cells; Epitopes; Event; Exhibits; Frequencies; Generations; Genes; Goals; Graft Rejection; Graft Survival; HLA Antigens; HLA-DP Antigens; HLA-DQ Antigens; Histocompatibility Antigens; Immune; Immune Targeting; Immune response; Immunologics; Immunology; Immunosuppression; Individual; Knowledge; Lead; Life; Ligation; Mass Spectrum Analysis; Measures; Mediating; Medical; Mission; Modeling; Molecular; Mutagenesis; National Institute of Allergy and Infectious Disease; Organ; Organ Transplantation; Organ failure; Outcome; Pathogenicity; Pathway interactions; Patients; Positioning Attribute; Protein Isoforms; Proteins; Proteomics; Public Health; Quality of life; Reagent; Research; Research Proposals; Resources; Retinal Cone; Risk; Signal Pathway; Site-Directed Mutagenesis; Solid; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Testing; Time; Transplant Recipients; Transplantation; Transplantation Immunology; Visualization; Work; allograft rejection; allotransplant; antibody-mediated rejection; cell type; cohort; comparative; donor-specific antibody; drug development; experience; experimental study; glomerular endothelium; glycosylation; graft dysfunction; human leukocyte antigen testing; human monoclonal antibodies; immune activation; immunogenicity; improved; in silico; innovation; knockout gene; novel; novel therapeutics; organ allocation; organ transplant rejection; pathogenic isoform; patient stratification; personalized medicine; pressure; prevent; prognostication; response; risk stratification; standard of care; stem; symposium; tool

PROJECT SUMMARY Organ transplantation is a standard-of-care treatment for patients with end-organ failure. Although graft survival has increased significantly over the years, many patients lose their life-saving transplant due to antibody- mediated rejection. Recent work demonstrated that the main target of these antibodies are donor HLA-DQ molecules. This observation is puzzling since the leading convention in the field considered HLA-DR, another type of HLA-class II molecules, as the leading “transplantation antigens”. It is now clear that the frequency and pathogenicity of antibodies against HLA-DQ is higher than HLA-DR (and HLA-DP, the third class II HLA molecules). Currently, there is no mechanistic explanation to these observations. Our central hypothesis is that HLA-DR, HLA-DQ, and HLA-DP were specialized, through evolutionary pressure, to control somewhat different pathways of immune activation. This can be likened to the 3 types of cone photoreceptor cell types that provide similar functionality but for different wavelengths to maximize sensitivity to color. Importantly, the vast majority of mechanistic studies focused on HLA-DR, and the assumption is that HLA-DQ and HLA-DP use identical immune pathways. Our long-term goal is to understand the mechanism leading to the increased immunogenicity and pathogenicity of HLA-DQ mismatches in allo-transplantation (compared with HLA-DR and HLA-DP). The objective is to decipher permissible from non-permissible HLA-DQ mismatches, and further to elucidate immune activation pathways that are preferentially stimulated by HLA-DQ allo-recognition. Specifically, in Aim 1, we will define the immunogenicity of HLA-DQ mismatches that lead to the development of donor-specific HLA-DQ antibodies in transplant recipients. We will use computational and experimental approaches including adsorption/elution and site directed mutagenesis studies to prognosticate qualitative characteristics of HLA-DQ epitopes. In Aim 2, we will compare immune activation pathways triggered by ligation of different HLA class II molecules. We will evaluate the 3 different mechanisms of the immune response: those mediated by qualities of the antibody itself; those transduced inwards, downstream of the ligated HLA class II molecules; and those elicited via the T cell receptor recognizing the different class II molecules. We will use cutting edge proteomic technology as well as CRISPR-Cas9 edited cells expressing only one HLA class II allele as innovative tools to interrogate these specific pathways. Taken together, this project will support two significant advancements in solid organ transplantation: personalized medicine with respect to organ allocation and immunosuppressive management, and identification of novel immune targets for drug development. The shortage of organs for transplantation, the medical and financial ramifications associated with the need to treat allograft rejection, and the impact of immunosuppression and graft dysfunction/loss on patient quality of life all highlight an unmet need for improving organ transplant outcomes. The proposed work is in line with the NIAID mission of conducting applied research to better understand, treat, and ultimately prevent transplant rejection.

项目摘要 器官移植是针对最终器官衰竭患者的护理标准治疗。虽然移植生存 多年来，由于抗体 - 介导的拒绝。最近的工作表明，这些抗体的主要靶标是供体HLA-DQ 分子。该观察结果是难题，因为该领域的主要公约认为HLA-DR，另一个 HLA级II分子的类型，作为主要的“移植抗原”。现在很明显，频率和 抗HLA-DQ抗体的致病性高于HLA-DR（和HLA-DP，第三类II HLA 分子）。当前，这些观察结果没有机械解释。我们的中心假设是 HLA-DR，HLA-DQ和HLA-DP是通过进化压力专门的，以控制一些不同 免疫激活的途径。这可以对提供的3种类型的锥形光感受器细胞类型喜欢 相似的功能，但对于不同的波长，可以最大程度地提高对颜色的敏感性。 重要的是，绝大多数机械研究集中在HLA-DR上，其假设是HLA-DQ HLA-DP使用相同的免疫途径。我们的长期目标是了解导致的机制 HLA-DQ不匹配在同种异体转移中的免疫原性和致病性提高（与 HLA-DR和HLA-DP）。目的是解密不可允许的HLA-DQ不匹配的许可，并且 进一步阐明了由HLA-DQ Allo-reckention刺激的免疫激活途径。 具体而言，在AIM 1中，我们将定义导致发展的HLA-DQ不匹配的免疫原性 移植受体中的供体特异性HLA-DQ抗体。我们将使用计算和实验性 包括增加吸附/洗脱和定向诱变研究的方法，以证明定性 HLA-DQ表位的特征。在AIM 2中，我们将比较由连接触发的免疫激活途径 不同的HLA II类分子。我们将评估免疫反应的三种不同机制： 由抗体本身的品质介导；那些向内翻译，下游的HLA II类 分子；以及通过T细胞受体引起的那些识别不同II类分子的受体。我们将使用 最先进的蛋白质组学技术以及CRISPR-CAS9编辑的单元仅表示一个HLA II类等位基因 作为询问这些特定途径的创新工具。综上所述，该项目将支持两个重要的 固体器官移植的进步：关于器官分配的个性化医学和 免疫抑制作用，并鉴定了新型药物开发的免疫靶标。 移植器官短缺，与需要相关的医疗和财务影响 治疗同种异体抑制，以及免疫抑制和移植功能障碍/损失对患者生活质量的影响 所有这些都强调了改善器官移植结果的未满足需求。拟议的工作与Niaid一致 进行应用研究以更好地理解，治疗和最终防止移植拒绝的使命。