TNFRSF13B polymorphisms and immunity to transplantation

Abstract: The proposed research investigates how genomic polymorphism of the TNFRSF13B locus predicts and potentially governs the character and outcome transplantation immunity in humans. The investigators recently found (de Mattos Barbosa et al., 2021) non-synonymous mutations of TNFRSF13B occur 5-fold more often in kidney transplant recipients that developed antibody- mediated rejection than in recipients with persistently healthy grafts. Since TNFRSF13B genotype determines production of natural antibodies, affinity-maturation, kinetics and persistence of elicited antibody production, the genotype is hypothesized to determine whether transplant immunity is dominated by bursts of high affinity pathogenic allospecific antibodies or by steady state low affinity allo-specific antibodies with graft protective functions (mostly in germline configurations). The proposed research will take advantage of access to a large pool of DNA samples from recipients of kidney transplants at the Michigan Genomics Initiative biorepository and those collected as part of the APOLLO study to connect genotypes with transplantation outcomes. We will determine whether allelic TNFRSF13B variants of known phenotype engender donor-specific B cell responses to organ allografts consistent with the function of the variant studying recipients recruited at several major transplant centers. The functional properties of the most important TNFRSF13B alleles will be confirmed and the mechanism ascertained by engineered tnfrsf13B mutations in mice and testing such mice as recipients of heterotopic cardiac allografts.