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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要器官移植是终末器官衰竭患者的标准治疗方法，尽管移植物存活。多年来显着增加，许多患者因抗体而失去了挽救生命的移植手术最近的研究表明，这些抗体的主要目标是供体 HLA-DQ。这一观察结果令人费解，因为该领域的主要惯例认为 HLA-DR 是另一种分子。类型的HLA-II类分子，作为主要的“移植抗原”，现在已经清楚，其频率和。 HLA-DQ 抗体的致病性高于 HLA-DR（以及 HLA-DP，第三类 II 类 HLA）目前，我们的中心假设是这些观察结果没有机械解释。 HLA-DR、HLA-DQ 和 HLA-DP 通过进化压力而专门化，以控制某些不同的这可以比作提供三种类型的视锥细胞类型。类似的功能，但针对不同的波长，以最大限度地提高对颜色的敏感度。重要的是，绝大多数机制研究都集中在 HLA-DR 上，并且假设 HLA-DQ 和 HLA-DP 使用相同的免疫途径，我们的长期目标是了解导致这一现象的机制。同种异体移植中 HLA-DQ 错配的免疫原性和致病性增加（与 HLA-DR 和 HLA-DP）的目的是区分允许的 HLA-DQ 不匹配和不允许的 HLA-DQ 不匹配。进一步阐明 HLA-DQ 同种异体识别优先刺激的免疫激活途径。具体来说，在目标 1 中，我们将定义导致发展的 HLA-DQ 错配的免疫原性我们将使用计算和实验来研究移植受者体内供体特异性 HLA-DQ 抗体的情况。包括吸附/洗脱和定点突变研究在内的方法来预测定性 HLA-DQ 表位的特征在目标 2 中，我们将比较连接触发的免疫激活途径。我们将评估 3 种不同的免疫反应机制：由抗体本身的性质介导；那些向内转导的、连接的 HLA II 类下游的抗体；分子；以及通过识别不同 II 类分子的 T 细胞受体引发的分子。尖端蛋白质组学技术以及仅表达一种 HLA II 类等位基因的 CRISPR-Cas9 编辑细胞作为探究这些特定途径的创新工具，该项目将支持两个重要的领域。实体移植组织的进步：器官分配和移植方面的个性化医疗免疫抑制管理，以及药物开发新免疫靶点的鉴定。移植器官的短缺、与需要相关的医疗和财务影响治疗同种异体移植排斥，以及免疫抑制和移植物功能障碍/丧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得到满足的需求。拟议的工作符合 NIAID 的要求。开展应用研究以更好地理解、治疗并最终预防移植排斥反应的使命。