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.

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