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The success of a kidney transplant largely depends on how well the donor’s and recipient’s tissues match. A poor match in so-called HLA proteins can trigger a strong immune response, leading to rejection of the transplanted organ. This thesis investigated how the recipient’s immune cells – specifically T cells – recognize donor HLA. We showed that the risk of T-cell-mediated rejection increases when these cells can recognize many different epitopes. An epitope is a specific feature on a foreign protein that can activate the immune system. In addition, we found that the increased risk on graft failure following a previous HLA immunization, including a previous transplantation, a blood transfusion, or a pregnancy, depends on the overlap in T-cell epitopes between the immunizing HLA and the HLA of the donor. Interestingly, in women with recurrent miscarriages, a higher presence of these T-cell epitopes appeared to have a protective effect on pregnancy outcome. This finding suggests that, in certain circumstances, a degree of difference between HLA proteins can actually be beneficial and induce tolerance. In the second part of this thesis, we showed that rejection is influenced not only by HLA proteins on the cell surface but also by HLA signal peptides: small fragments of the HLA protein that are not part of the HLA proteins on the cell surface. In patients with a past cytomegalovirus infection, these peptides seem to trigger early rejection, likely because of similarities between viral epitopes and HLA epitopes. Combined, these insights could help doctors select the most suitable donor and better predict the risk of rejection, ultimately improving outcomes for kidney transplant patients.