Background: Recently, mismatches at the HLA-DQα/β heterodimer level have been recognized as important in transplant immunologic risk. In particular, donor heterodimers containing the DQα05 chain appear to be associated with a higher risk of developing de novo donor-specific antibodies (dnDSA).
Methods: This retrospective cohort study included 227 pediatric kidney transplant recipients at Stanford Children’s Health (2010–2018) with ≥12-month follow-up through September 2022. HLA-DQ heterodimers were paired by linkage disequilibrium with DRB1 alleles. A DQα05 mismatch was defined when the donor expressed a DQα05-containing heterodimer not present in the recipient. dnDSA was defined as a post-transplant HLA-DQ antibody with MFI ≥3000 and absent pre-transplant. Antibody testing was performed at 0, 1, 2, 3, 6, 12 months, annually, and as clinically indicated. Kaplan-Meier survival and frequency analysis assessed the association between specific HLA-DQ heterodimer mismatches and dnDSA formation.
Results: A total of 227 patients were included (median age 14 years [IQR 4–17]; 49% female; 23% living donor). The median follow-up time was 73 months (IQR 58–96). 65/227 (28.6%) developed dnDSAs targeting HLA-DQ. Kaplan-Meier analysis showed that recipients with DQα05 mismatches were significantly more likely to develop dnDSA over time than those without DQα05 mismatches (p < 0.0001).

Mismatch frequency analysis demonstrated that specific heterodimer pairs were more commonly associated with dnDSA. The highest dnDSA formation rates were observed in recipients mismatched for DQA1*05/DQB1*03 (33%) and DQA1*05/DQB1*02 (31%), suggesting these specific DQα05 heterodimer mismatches may confer greater risk.

Conclusion: DQα05 heterodimer mismatch was strongly associated with the formation of HLA-DQ dnDSA in our cohort. Identifying DQ mismatches that carry a higher risk of dnDSA formation may help optimize allocation systems, guide organ selection for sensitized patients, and support immunologic risk stratification post-transplant to improve graft outcomes.