The number of amino acid triplet differences between patient and donor is predictive for the antibody reactivity against mismatched human leukocyte antigens.

Background. The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) and the number of amino acid sequence mismatches was analyzed in patients who rejected a kidney transplant (n146). Methods. A similar analysis was performed for the antibody production of women against the paternal HLA antigens of their child (n1,397). The amino acid sequence (triplet) differences were analyzed using the HLAMatchmaker algorithm. Results. In both groups, a positive correlation was found between the number of triplet mismatches and the percentage of individuals producing antibodies (P<0.0001). If zero triplet mismatches were present, no antibodies were formed in all cases. When 11 or 12 triplet mismatches were present, 94% of the transplant patients produced antibodies against the donor. In pregnancy, 11 or 12 triplet mismatches led to 27% of the women producing specific antibodies. Conclusions. These results indicate that the immunogenicity of the fetus is lower than that of a rejected kidney and that analysis of the number of triplet mismatches can predict the antibody reactivity against the mismatched HLA antigens. Donor-specific human leukocyte antigen (HLA) antibodies can be detected in individuals who have been immunized as a result of pregnancies, failed transplants, or blood transfusions. During pregnancy, women can produce antibodies directed against the paternal HLA antigens of the child. The role of these antibodies in pregnancy is unclear. It is suggested that recognition of paternal HLA antigens of the child might be involved in a maternal immunologic adaptation required to protect the fetal allograft (1). Antibodies directed against the paternal HLA antigens of the child are generally detected in only 15% to 30% of women. Potential factors contributing to the induction of antipaternal antibodies are the number of fetal cells passing through the placenta, the number of HLA mismatches between child and mother, the development of anti-idiotypic antibodies directed against anti-HLA antibodies (2), or cytokine polymorphism in the mother (3). In cadaveric transplantation, a serologic crossmatch test between kidney donor and transplant recipient is routinely performed to avoid hyperacute rejection caused by donor HLA-specific antibodies. However, acute rejection leading to early graft loss and chronic rejection remain major problems. A better understanding and prediction of the humoral response may be of benefit for renal transplant recipients. In previous studies, we could demonstrate that the immunogenicity of a particular HLA mismatch, as measured by the induction of alloantibodies, depends on the HLA phenotype of the donor as well as that of the recipient ( 4–6 ). This differential immunogenicity might be explained by specific amino acid sequence differences between the HLA alleles of donor and recipient. These amino acid sequence differences can be analyzed by a computer algorithm developed by Duquesnoy (7) that defines the HLA-A and HLA-B mismatches by triplets of amino acid residues on alloantibody accessible sites of HLA molecules. The program converts each HLA class I allele into a string of linear amino acid triplets and then determines which donor amino acid triplets are shared or not shared between donor and recipient. The program is based on the concept that no antibodies are formed against triplets of amino acids that are shared between donor and recipient. In the present study, we determined whether in patients who rejected a kidney transplant a correlation exists between the antibody production against the mismatched donor HLA antigens and the number of triplet mismatches between patient and donor. A similar approach was used for the incidence of antibody production by women against the mismatched paternal HLA antigens of the child.