Human Leukocyte Antigen (HLA) Typing in Hematopoietic Stem Cell Transplantation

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Hematopoietic stem cell transplantation (HSCT) is an established therapeutic option for patients with high-risk hematologic malignancies and bone marrow failure syndromes. It involves the transplantation of blood stem cells to reestablish hematopoietic function in patients who have undergone bone marrow ablation. A key factor determining the success of allogeneic HSCT is histocompatibility between the donor and recipient. Differences in human leukocyte antigen (HLA) genes that regulate immune responses lead to graft rejection or graft-versus-host disease (GVHD). Therefore, HLA typing is essential for identifying an optimal donor-recipient pair.

The HLA gene complex encodes major histocompatibility complex (MHC) proteins that regulate immune responses through the presentation of peptides to T cell receptors. These genes are highly polymorphic, with thousands of alleles identified. Matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 alleles, referred to as 8/8 HLA match, between sibling donors and recipients is ideal. However, only 30% of patients have HLA-matched siblings. For others, unrelated donors (URDs) or umbilical cord blood units are options. High-resolution typing methods for HLA alleles in donors and recipients enable the selection of optimal URDs with permissible mismatches.

HLA typing approaches include serological and DNA-based methodologies. Serological typing utilizing HLA antigen-specific antibodies can identify broad HLA antigen groups but lacks specificity. DNA-based methods like sequence-specific oligonucleotide probing (SSOP) and sequencing-based typing (SBT) enable high-resolution HLA allele identification. For URD identification, individuals are typed for HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci at intermediate resolution initially, followed by high-resolution confirmation typing of matched donors. Specialized algorithms and search filters in registries like Be The Match facilitate URD selection while considering factors like HLA match grade, donor age, and infectious disease markers.

GVHD and graft rejection risks correlate with the degree of HLA mismatch. HLA mismatches in the graft-versus-host vector provoke stronger alloreactive T cell responses. Permissible mismatches are locus-specific. A single HLA allele or antigen mismatch may be tolerated depending on the locus. HLA match thresholds for URDs are allele-level typing for HLA-A, HLA-B, HLA-C and antigen-level typing for HLA-DRB1. Allele-level mismatches at HLA-A, HLA-B, HLA-C and antigen-level mismatches at HLA-DRB1 are associated with higher GVHD risks without impacting engraftment or graft failure risks. T cell depletion of the graft and post-transplantation immunosuppression manage GVHD risks. High-resolution HLA typing and selection of URDs meeting permissible HLA match thresholds is key for successful outcomes after allogeneic HSCT.

Ongoing research focuses on refining HLA typing methods and match thresholds for specific patient groups. Novel cell therapies also utilize HLA matching principles for immunotherapy applications beyond HSCT. Overall, HLA typing forms the cornerstone for donor selection in allogeneic HSCT, enabling curative therapy for many patients lacking matched sibling donors.