HLA Mismatching Strategies for Solid Organ Transplantation - A Balancing Act

Abstract

HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient's HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient's antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor.

Keywords: HLA matches; HLA mismatches; donor-specific antibody; immunogenicity; match probability; repeated mismatches; sensitization.

Figure 1

Gene organization of HLA-DR haplotypes. DR haplotypes have varying numbers of genes, some of which encode a polypeptide chain (filled boxes) and others are pseudogenes that have no detectable product (open boxes). DR molecules are comprised of two polypeptide chains, an α chain and a β chain. All DR haplotypes have a DRA gene that encodes the relatively invariant α chain and a DRB1 gene that encodes the β chain of the DR1-DR18 antigens. Some haplotypes carry an additional gene, DRB3, 4, or 5, that encodes the β chain of the DR52, 53, or 51 molecules, respectively. DR haplotypes can be grouped into families defined by the number of DRB genes present as shown in the diagram.