IDENTIFICATION OF HLA-DR CREGS AND IMPLICATIONS FOR TRANSPLANTATION.

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#169
IDENTIFICATION OF HLA-DR CREGS AND IMPLICATIONS FOR TRANSPLANTATION.
Renato M. Vega, CHT , Donna P. Lucas, CHS , Christina L. Newman, CHT , David S. Nordman, CHS , Mary S. Leffell, PhD and Andrea A. Zachary, PhD . Baltimore MD, USA, Johns Hopkins University School of Medicine, 21205-2222, Medicine and Stamford CT, USA, Orchid Diagnostics, 06902 .

HLA cI CREGs are recognized and applied in some organ allocation schemes. However, characterization and clinical importance of cII CREGs has not been established. We examined ELISA reactivity patterns of 364 cII-specific sera. Certain specificities occurred together in high frequency: among sera specific for DR1, 74% also reacted with DR10, 64% with DR2, and 44% with DR9; anti-DR2 occurred with Ab to DR10 (68%) and DR9 (42%); anti-DR7 with Ab to DR9 (90%); Ab to DR8 and DRw52 (81%), and anti-DRw53 with anti-DR10 (68%). The frequencies of 26 pairs of specificities were significantly different (χ²= 730.2, P<0.0001) from those expected from random distribution. Associations contributing >5% to the χ² were, in descending order, DR7-9, DR8-w52, DR1-10, DR2-10, DR10-w53, and DR1-2. Cell lines were used to absorb 10 different sera for a total of 26 absorptions to confirm crossreactivity. Untreated and absorbed sera were then tested simultaneously either by ELISA or Luminex. Together the reactivity patterns and absorptions suggest the following DR CREGs: DR1-2-9-10, DR1-4, DR3-5-6, DR4-10-w53, DR5-8-w52, and DR7-9. This was further confirmed by epitope spreading seen in sequential samples from several patients and by amino acid sequences with fewer differences occurring with intra-CREG mismatches. Inter-CREG mismatches were more immunogenic than intra-CREG ones. Mismatches for a member of the DRw52 or 53 families resulted in reactivity to the whole CREG in 85% of the patients lacking an antigen in that CREG vs. 27-34% intra-CREG sensitization . These data suggest that certain DR mismatches represent higher risks for antibody-mediated rejection and that matching for DR CREGs could reduce humoral sensitization and improve graft survival.