Predicting HLA class I alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms.

BACKGROUND Knowledge of the human leukocyte antigen (HLA) amino acid (AA) sequence combined with crystallographic structural data may enable prediction of the relative immunogenicity of individual donor/recipient HLA mismatches. METHODS Multiple sera from 32 highly sensitized patients awaiting kidney transplantation were screened using Luminex/single-antigen beads to determine the HLA-specific antibody levels against mismatched HLA class I specificities. A computer program was developed to allow intralocus and interlocus comparison of mismatched HLA-A and -B specificities with corresponding recipient HLA class I type, and to determine the number, position, and physiochemical disparity (hydrophobicity and electrostatic charge) of polymorphic AA. RESULTS HLA-specific antibody was detected against 1666 (85%) of the 1964 mismatched HLA specificities evaluated, with a close correlation between increasing number of AA polymorphisms and the presence and magnitude of the alloantibody response (P<0.0001). Hydrophobicity and electrostatic charge disparity scores were independent predictors of alloantibody production (adjusted P=0.0009 and P=0.0005, respectively). Mismatched specificities with physiochemical scores within the first decile of the scale led to weak alloantibody responses (median fluorescence intensity 2330), whereas those with scores above the sixth decile led to strong alloantibody production (median fluorescence intensity >10,000). CONCLUSION Differences in AA number, hydrophobicity, and electrostatic charge between HLA class I specificities enable prediction of donor HLA class I types with low immunogenicity for a given recipient.