TNFRSF13B polymorphisms and immunity to transplantation

TNFRSF13B 多态性与移植免疫

基本信息

批准号：
10734879
负责人：
MARILIA Isabel CASCALHO
金额：
$ 80.97万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734879
关键词：
5&apos Untranslated Regions Acute Address Affinity Alleles Alloantigen Antibodies Antibody Formation Antibody Response Antigens Avidity B-Lymphocytes Binding Biopsy Cardiac Cell Separation Cell physiology Cells Characteristics Chronic Clinical Clonal Expansion Clone Cells Complement Complement Activation Complement Factor H Development Discrimination Dominant-Negative Mutation Engineering Enrollment Equilibrium Evolution Frequencies Gene Expression Genes Genetic Polymorphism Genomics Genotype Glycocalyx Health Heart Transplantation Homologous Gene Human Immune Immune response Immunity Injury Interleukin-10 Investigation Isoantibodies Kidney Transplantation Kinetics Knockout Mice Mammals Mediating Michigan Mus Mutate Mutation Organ Transplantation Outcome Pathogenicity Pathology Phenotype Population Probability Production Properdin Property Publications Research Research Personnel Resistance Risk Role Sampling Serum Shapes Specificity Spliced Genes Testing Time Tissue Grafts Transcript Transplant Recipients Transplantation United States National Institutes of Health Variant Wild Type Mouse allotransplant antibody-mediated rejection cohort donor-specific antibody experience genetic analysis graft function heart allograft isoimmunity natural antibodies nonsynonymous mutation pathogen plasma cell differentiation receptor response trait transcription factor

项目摘要

Abstract: The proposed research investigates how genomic polymorphism of the TNFRSF13B locus predicts and potentially governs the immune response to and outcomes of transplantation. The investigators (de Mattos Barbosa et al., 2021) recently found that non-synonymous mutations of TNFRSF13B occur 5-fold more frequently in kidney transplant recipients that develop antibody-mediated rejection than in recipients with persistently healthy grafts. The working hypothesis of this application is that TNFRSF13B polymorphism shapes B cell responses to allotransplantation in ways that determine pathogenicity of the responses. Since affinity-maturation, kinetics, self-non-self discrimination and persistence of elicited antibody production have been connected with TNFRSF13B function, these characteristics will be evaluated in allo-specific B cells isolated from kidney transplant recipients. Because TNFRSF13B is among the most polymorphic genes in humans and other mammals, the proposed research will draw on diverse pools of kidney transplants already enrolled in the Michigan Genomics Initiative, and in the NIH APOLLO study to connect genotypes with transplantation outcomes. The results obtained with these cohorts will be verified by analysis of genotypes and outcomes of subjects in two major NIH studies, DeKAF and GEN03. The large number of kidney transplant recipients enrolled in the aforementioned studies will provide a vast pool from which the phenotype and implications for transplantation of the most common allelic TNFRSF13B variants can be identified. The functional properties of the most important TNFRSF13B alleles in turn will be confirmed and the mechanism ascertained by engineering tnfrsf13B mutations in mice and testing B cell functions and outcomes of heterotopic cardiac allotransplants.

抽象的：拟议的研究调查了 TNFRSF13B 的基因组多态性如何位点预测并可能控制免疫反应和结果移植。研究人员（de Mattos Barbosa 等人，2021）最近发现 TNFRSF13B 的非同义突变在肾脏中发生的频率是原来的 5 倍发生抗体介导排斥反应的移植受者比患有抗体介导排斥反应的受者持续健康的移植物。本申请的工作假设是 TNFRSF13B 多态性以决定的方式塑造 B 细胞对同种异体移植的反应反应的致病性。由于亲和力成熟、动力学、自我非自我引起的抗体产生的歧视和持续性与 TNFRSF13B 功能，这些特征将在同种异体特异性 B 细胞中进行评估从肾移植受者中分离出来。因为 TNFRSF13B 是最人类和其他哺乳动物的多态性基因，拟议的研究将借鉴已加入密歇根基因组计划的不同肾移植库， NIH APOLLO 研究将基因型与移植结果联系起来。这这些队列获得的结果将通过基因型和结果分析进行验证 NIH 两项主要研究 DeKAF 和 GEN03 中的受试者数量。肾脏数量较多参与上述研究的移植受者将提供大量来自最常见等位基因的表型及其对移植的影响可以鉴定 TNFRSF13B 变体。最重要的功能特性 TNFRSF13B 等位基因将依次得到确认并确定其机制在小鼠中设计 tnfrsf13B 突变并测试 B 细胞功能和结果异位心脏同种异体移植。