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Predicting HLA Class II Alloantigen Immunogenicity From the Number and Physiochemical Properties of Amino Acid Polymorphisms

Background. We have shown previously that human leukocyte antigen (HLA) class I immunogenicity can be predicted by the number, position, and physiochemical differences of polymorphic amino acids (AAs). We have now modeled the structural and physiochemical polymorphisms of HLA class II alloantigens and correlated these with humoral alloimmunity in sensitized patients awaiting kidney transplantation. Methods. Sera obtained from 30 patients with high levels of IgG HLA-specific antibodies were screened using single-antigen HLA antibody detection beads. A computer program was developed to determine the number of AA mismatches (after interlocus and intralocus subtraction) and their hydrophobicity and electrostatic mismatch score for each mismatched HLA-DR and -DQ specificity. Regression methods were used to compare these variables with the occurrence and magnitude of alloantibody responses. Results. HLA-specific antibody was detected against 879 (55%) of 1604 mismatched HLA specificities evaluated. There was a strong correlation between increasing number of AA mismatches and the occurrence (P<0.001, odds ratio 3.85 per AA) and magnitude of alloantibody responses (P<0.001); only 6% of alloantigens with 0 to 2 mismatched AA-induced alloantibody (median fluorescence intensity 37) compared with 82% of alloantigens with more than or equal to 20 mismatched AAs (median fluorescence intensity 9969). Hydrophobicity and electrostatic mismatch scores also correlated closely with alloantibody response (P<0.001), but neither variable had independent predictive value over the number of AA mismatches alone. Conclusion. Differences in the number of polymorphic AA mismatches and their physiochemical properties for a given recipient HLA type are strong predictors of class II alloantigen immunogenicity and alloantibody response before kidney transplantation.