HLA mismatches and the production of alloantibodies
HLA mismatches are not only the trigger for alloreactive T cells to destroy the transplant parenchyma, they also lead to the formation of alloreactive anti-HLA antibodies; and together they contribute to acute and chronic rejection, and the eventual immunologically-mediated transplant loss. But it is not the number of mismatched antigens what stimulate the immune system, but rather the antigenic differences, even of one single amino acid, between the HLA molecules of the donor and recipient. Thus, the traditional model of HLA matching, counting the absolute number of HLA mismatches, fails to identify mismatches that are more immunogenic from those less immunogenic. For instance, HLA-DR mismatches appear to confer poorer prognosis than mismatches in class I HLA antigens. Therefore, two mismatches in HLA I class molecules will not have the same immunological impact than two mismatches in class II HLA molecules. Thus, achieving the best possible antigenic match, or the most acceptable antigenic mismatch (and likely least immunogenic), according to the HLA matchmaker principle shall instead reflect more realistically the impact of HLA mismatch in solid organ transplantation.