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： 这项拟议的研究调查了TNFRSF13B的基因组多态性 基因座预测并潜在地控制对以下疾病的免疫反应和结果 移植。调查人员(De Mattos Barbosa等人，2021年)最近发现 TNFRSF13B非同义突变在肾脏中发生的频率是对照组的5倍 发生抗体介导排斥反应的移植受者比 持久健康的移植物。该应用程序的工作假设是TNFRSF13B 基因多态性决定了B细胞对同种异体移植的反应 这些反应的致病性。亲和力--成熟、动力学、自我--非我 诱导抗体产生的辨别力和持久性与 TNFRSF13B的功能，这些特性将在异种特异性B细胞中进行评估 从肾移植受者身上分离出来的。因为TNFRSF13B是最多的 人类和其他哺乳动物的多态基因，这项拟议的研究将借鉴 密歇根基因组学倡议已经登记了不同的肾脏移植池， 并在NIH阿波罗研究中将基因类型与移植结果联系起来。这个 从这些队列中获得的结果将通过对基因类型和结果的分析来验证 在NIH的两项主要研究中，DeKAF和GEN03的受试者。肾的数量多 在上述研究中登记的移植受者将从 其中最常见的等位基因的表型及其对移植的意义 可以确定TNFRSF13B变异体。最重要的函数性质 TNFRSF13B等位基因将依次得到确认，其机制将通过 在小鼠中设计TNFRSF13B突变并检测B细胞功能和结果 同种异位心脏移植。