The highly sensitized patient remains an enigma for kidney transplantation. Not only is it difficult to find suitable donors with negative crossmatches, but the transplant outcome is less successful for such patients. This problem affects especially African-American patients. HLA is considered the primary system of transplantation antigens recognized by antibodies in sera from sensitized patients. Each HLA molecule contains a complex array of multiple antigenic epitopes categorized as private and public determinants and amino acid sequencing has revealed extensive allelisms at the residue level. Most highly sensitized patients maintain, however, a rather restricted repertoire of antibody specificity towards generally high-frequency antigenic determinants. These studies deal with the determination of the antibody specificity spectrum in highly sensitized patients so that donors can be identified with acceptable mismatches and this will improve graft outcome. Three interrelated projects are proposed: 1) Conduct an HLA antibody specificity analysis of pre-transplant sera from highly sensitized African-American kidney transplant patients and determine how donor HLA mismatch acceptability affects graft outcome; this will be a large collaborative effort between histocompatibility laboratories nationwide; 2) Implement an acceptable mismatch strategy to select donors for highly sensitized patients on the transplant waiting list. This project will be conducted at the regional level and involves the participation of transplant centers in UNOS Region 2; 3) Determine the relative immunogenicity of HLA class I determinants and its clinical relevance to kidney transplant survival. The study will be done in collaboration with UCLA investigators and involves the UNOS kidney transplant database. The investigators expect that the results of these studies will increase our understanding of HLA compatibility and benefit donor selection strategies for patients awaiting kidney transplantation.
