Genetic Polymorphisms in Follicular Helper T Cell–Related Molecules Predispose Patients to De Novo Donor-Specific Antibody Formation After Kidney Transplantation

Abstract

Risk prediction of de novo donor-specific antibody (dnDSA) formation is crucial for understanding the long-term prognostic impact of kidney transplantation (KT). Recently, follicular helper T (Tfh) cells, a subtype of CD4+ T cells, have been reported to play an important role in dnDSA formation after solid organ transplantation. Given the growing recognition of the importance of Tfh cells in generating a strong humoral immune response, we examined whether polymorphisms in Tfh cell-related molecules were associated with dnDSA formation after KT. Eighty-three patients who underwent living-donor KT between January 2013 and February 2020 at Hiroshima University Hospital were included in the study. Six Tfh cell-related molecules (BCL6, CXCR5, CXCL13, ICOS, CD40L, and IL21) that are important for Tfh cell differentiation and maturation in secondary lymphoid tissues were investigated. CTLA4, which is important for Tfh-cell activation, was also investigated. Single nucleotide polymorphisms (SNPs) in the genes for these molecules were detected using Taq Man SNP genotyping and evaluated for their association with dnDSA formation after KT. Of the 83 KT recipients, 8 developed dnDSAs during the observation period. No statistically significant differences were observed in the baseline characteristics between patients with and without dnDSA formation, except for donor age. Among the 7 Tfh cell-related molecules, the incidence of dnDSA formation was associated with CXCR5 and CTLA4 SNPs. Furthermore, combining these 2 SNPs enabled more significant stratification of dnDSA formation. Our findings indicate that genetic polymorphisms in Tfh cell-related molecules are predisposing factors for dnDSA formation after KT.