Patients With Bw4 and Bw6 Antibodies can Participate in Clinical Xenotransplantation Trials

BACKGROUND: With clinical xenotransplantation now underway, optimal patient selection is critical for achieving successful outcomes. Candidates with antibodies targeting Bw4 and Bw6 epitopes on HLA molecules often experience prolonged wait times for allotransplantation because of high calculated panel reactive antibody levels. We investigated whether these antibodies cross-react with class I swine leukocyte antigen (SLA) molecules and could therefore pose a barrier to xenotransplantation. METHODS: We performed sequence alignment and structural modeling to assess the presence of Bw4 and Bw6 epitopes in class I SLA proteins. Human sera containing anti-Bw4 or anti-Bw6 antibodies were tested for reactivity against SLA molecules encoded by 5 haplotypes from pigs we study in xenotransplantation. Genetically engineered pig renal endothelial cells and a prototype panel of SLA-coated beads served as antigenic targets in flow cytometry assays. RESULTS: Structural analysis confirmed the absence of Bw4 and the presence of modified Bw6 motifs in SLA molecules. Despite the potential epitope conservation, anti-Bw6 sera showed no significant IgG binding to SLA, possibly because of residues adjacent to the canonical epitope. One anti-Bw4 patient showed IgG reactivity to SLA alleles lacking Bw4 or Bw6, implicating a distinct epitope. IgM reactivity was broadly observed across sera. CONCLUSIONS: These findings indicate that the SLA of at least some pigs will not exhibit cross-reactivity with anti-Bw4 and anti-Bw6 antibodies. Incorporating detailed, epitope-level histocompatibility testing may allow these highly sensitized patients, access to xenotransplantation.