The humoral immune response against an HLA class I allodeterminant correlates with the HLA-DR phenotype of the responder.

Abstract

The genetic basis for control of alloantibody responses against foreign HLA histocompatibility antigens has never been delineated. The most likely postulate would be that HLA class II alloantigens of the host regulate the response through their ability to present processed HLA allopeptide fragments for the cognate interaction between CD4+ T lymphocytes and B lymphocytes that leads to IgG antibody synthesis. We have analyzed our allosensitized transplant patient population with regard to humoral responsiveness to a serologically defined public HLA class I epitope, Bw4. Peptides representing the linear sequence of the Bw4 epitope (amino acids 74-86) and the alternative Bw6 epitope were synthesized and assayed for binding to a panel of HLA homozygous lymphoblastoid B cells using a quantitative fluorescence binding assay. We found that 73% of patients who have produced a HLA-Bw4-specific alloantibody express either the HLA-DRB1*01 or HLA-DRB1*03 alloantigen; 19% of the remaining responders expressed HLA-DRB1*04. Analysis of the United Network for Organ Sharing Transplant Registry indicated that the survival of cadaver renal allografts mismatched for Bw4 was significantly compromised in sensitized DRB1*01+ or DRB1*03+ recipients (P<0.01). In vitro, the Bw4 peptide bound strongly to DRB1*01+ and DRB1*03+ lymphoblastoid B cells; no similar binding was observed with Bw6 peptide. These findings were confirmed using murine fibroblast lines transfected with HLA-DR alpha/beta genes and by solid-phase enzyme-linked immunosorbent assay using purified HLA-DR alloantigen. We conclude that there are at least two human Ir genes, HLA-DRB1*01 and HLA-DRB1*03, that confer a high risk for both humoral allosensitization and renal allograft failure in situations of HLA-Bw4 incompatibility. These findings may be of future benefit in devising new antigen matching strategies for reducing the risk of humoral HLA allosensitization and chronic allograft rejection.