Why would a clinician order a high‑resolution human leukocyte antigen (HLA)‑DRB1 test?

Why Order an HLA-DRB1 High-Resolution Test?

HLA-DRB1 high-resolution testing is ordered primarily to optimize donor-recipient matching for hematopoietic stem cell transplantation, as mismatches at this locus significantly increase mortality risk, acute graft-versus-host disease, and transplant-related complications. 1

Primary Clinical Indications

Hematopoietic Stem Cell Transplantation (Most Common)

Unrelated Donor Selection

• Donors with the highest likelihood of matching should undergo complete HLA-A, -B, -C, and -DRB1 high-resolution testing to select the best HLA match. 1
• Mismatches at HLA-A and -DRB1 are less well-tolerated than mismatches at HLA-B or -C, making DRB1 matching particularly critical for survival outcomes. 1
• Each HLA mismatch increases mortality risk in a dose-dependent manner: 10% lower survival per mismatch in low-risk disease patients and 5% lower survival per mismatch in high-risk disease patients. 1, 2
• DRB1 matching decreases the risk of acute GVHD (relative risk 0.58), transplant-related mortality (relative risk 0.66), and overall mortality (relative risk 0.71). 3

Cord Blood Unit Selection

• Cord blood units must be typed for DRB1 at high resolution (minimum requirement), with HLA-C typing strongly recommended. 1, 4
• Among cord blood transplants mismatched at 2 loci, mismatching at HLA-C and -DRB1 carries the highest mortality risk. 1
• High-resolution typing ensures potential allele-level mismatches are well-characterized and allows better evaluation of HLA matching impact. 1

When Optimal Matching Cannot Be Achieved

• If an HLA-A, -B, -C, and -DRB1 matched donor cannot be identified after initial screening, additional loci including -DQB1 and -DRB3/4/5 should be typed to select the optimal mismatched donor. 1

Solid Organ Transplantation

Kidney Transplantation

• High-resolution HLA genotyping is recommended (Grade 1A) for correct assessment of anti-HLA antibody specificity to the donor. 1
• This testing enables accurate identification of donor-specific antibodies (DSA) that predict antibody-mediated rejection and graft loss. 1
• HLA-DQ mismatches are increasingly recognized as critical risk factors, with 54-77% of patients with de novo DSA developing antibodies against HLA-DQ. 2

Liver Transplantation

• High-resolution HLA-DRB1 genotyping is recommended (Grade 2C) for posttransplant DSA assessment. 1
• Complement-fixing DSAs are associated with increased risk of allograft loss and rejection. 1

Heart and Lung Transplantation

• High-resolution genotyping is recommended (Grade 1B for heart, 1B for lung) for correct anti-HLA antibody specificity assessment. 1

Technical Considerations

What "High-Resolution" Means

• High-resolution typing focuses on alleles encoding proteins found on the cell surface and the antigen recognition site of HLA molecules. 1
• The antigen recognition site is the "active" portion that binds peptide antigens and interacts with T-cell receptors. 1
• Alleles identical in the antigen recognition site domain do not have immunologic differences and are considered matched. 1

Methodological Approaches

• DNA-based methods including sequence-specific oligonucleotide probe hybridization, direct sequencing, and next-generation sequencing provide allele-level resolution. 5, 6, 3
• Single-tube amplification strategies followed by sequencing can provide unambiguous typing in approximately 71% of cases, with ambiguities resolvable through additional sequencing. 7

Clinical Context Affecting Testing Strategy

Disease Risk Status

• Mismatching has greater impact on mortality in early-stage/low-risk disease recipients compared to intermediate-stage or advanced disease patients. 1
• More mismatching may be acceptable in advanced disease cases where rapid transplantation is needed. 1

HLA-Sensitized Patients

• Testing beyond HLA-A, -B, -C, and -DRB1 supports donor selection to avoid potential graft failure risk. 1
• This is particularly important in patients with prior sensitizing events (pregnancies, blood transfusions, previous transplants). 2

Common Pitfalls to Avoid

• Do not rely on antigen-level typing alone for DRB1 – allele-level mismatches have similar adverse effects as antigen-level mismatches on transplant outcomes. 1
• Do not delay urgent transplantation – balance high-resolution typing costs and time against the patient's medical urgency, potentially using targeted loci screening strategies. 1
• Do not assume DRB1 matching alone is sufficient – it must be part of comprehensive HLA-A, -B, -C, and -DRB1 matching for optimal outcomes. 1
• Do not overlook cost considerations – enlist HLA expert assistance to maximize resources by focusing on donors most likely to match the patient. 1