Innovative approaches for HLA-matching and immune risk stratification in kidney transplantation

Renal transplantation is the first-choice treatment for end-stage renal disease. The importance of HLA-matching has been clearly established and the extent of HLA mismatching correlates with graft outcome. Despite the excellent short-term outcome, the outcome is hampered in the long-term. This is attributed in large to graft rejection caused by antibodies against immunogenic antigens and epitopes of the donors HLA type.

In this PhD project we will develop a sequencing workflow that allows defining the degree of HLA mismatching to an epitope level. In order to uncover the complete HLA genotype of donor/recipient pairs we will define a PCR setup and typing method with third-generation single-molecule real time sequencing (TGS) and translate this technology to clinical application. We will apply this method on the IWT-TEMPLATE cohort of 1000 kidney donor/recipient pairs. This will be done, not only for HLA-A, -B and -DR but also for the HLA-C,-DQ, and -DP loci. In a second part we will correlate these HLA typing data, interpreted to the epitope level, with graft outcome. We will evaluate the epitope specificities of patients that have pre-transplant and/or de novo anti-HLA antibodies, as defined with sensitive xMAP methods. The integration of these data will help us to determinate high-risk immunogenic epitope combinations in a given donor-recipient pair. Once defined, these immunogenic donor recipient combinations can be used to establish novel renal allocation algorithms.