De klinische betekenis van HLA mismatch load bij nier- en longtransplantatie

The aims of the PhD project: The following questions will be investigated in this PhD project: Which mismatched HLA epitopes are immunodominant in the development of an HLA antibody response in kidney transplantation? Why do the same mismatched HLA epitopes not always generate an antibody response? What are the risk factors for retransplanting patients who have a prior failed transplant? These questions are part of the following topic: 'Kidney transplantation is the treatment of choice for most patients suffering from end-stage renal disease (ESRD). HLA disparity between donor and recipient affects transplant immunity and consequently has an impact on graft outcome. One of the alloimmune mechanisms is the development of de novo donor specific antibodies (dnDSA), which represents a risk factor for humoral transplant rejection. This antibody-mediated rejection (ABMR) is a major cause of premature graft loss in kidney transplantation. As HLA antibodies are now recognized as being specific for epitopes and donor-recipient HLA mismatch at the amino acid level can now be determined, epitope-based permissible mismatching could be a new strategy. Although our study (Daniëls et al., Transplant Immunology, 2018) suggests that the total epitope mismatch load could be the determining factor in the risk of HLA antibody formation, it is clear that we lack data on the immunogenicity of the epitope mismatches. It could be that immunogenicity is not merely a quantitative issue, but that one or only a few epitope mismatches are sufficient to induce an antibody response. Maybe, the higher number of epitope mismatches only enhances the chance to include immunodominant epitopes. HLA epitope mismatches can be used as a risk assessment tool at time of transplantation and for post-transplantation follow-up, to evaluate those patients at the highest risk of HLA antibody formation. This could be especially valuable in young and paediatric kidney recipients, who will probably need more than one kidney allograft in their lifetime'