TNFRSF13B polymorphisms and immunity to transplantation

TNFRSF13B 多态性与移植免疫

• 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
• 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' 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

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.

摘要： 这项研究调查了TNFRSF13B基因组多态性如何影响人类的免疫功能。 基因座预测并可能控制免疫反应和结果 移植研究人员（de Mattos巴博萨等人，2021）最近发现， TNFRSF13 B的非同义突变在肾脏中的发生频率高5倍 发生抗体介导的排斥反应的移植受者比 持续健康的移植物。本申请的工作假设是TNFRSF13 B 多态性影响B细胞对同种异体移植的反应， 反应的致病性。由于亲和性成熟，动力学，自我非自我 引起抗体产生的辨别力和持久性与 TNFRSF13 B功能，将在同种异体特异性B细胞中评价这些特征 从肾移植受者身上分离出来的因为TNFRSF13B是目前 人类和其他哺乳动物的多态性基因，拟议的研究将借鉴 密歇根基因组计划已经登记了各种各样的肾脏移植， 以及在NIH APOLLO研究中将基因型与移植结果联系起来。的 这些队列获得的结果将通过分析基因型和结果进行验证 两项主要的NIH研究DeKAF和GEN 03中的受试者。大量的肾脏 参加上述研究的移植受者将提供一个巨大的游泳池， 其中最常见的等位基因的表型和移植的意义 可以鉴定TNFRSF13B变体。最重要的功能特性 TNFRSF13 B等位基因将被证实，并通过以下方法确定其机制： 在小鼠中工程化tnfrsf13 B突变并测试B细胞功能和 异位心脏移植