HLA-C, HLA-DP and HLA-DQ are thought to be benign due to low expression and few initial negative studies. Historically, most allocation programs used HLA-A, HLA-B and HLA-DR antigens for matching. With the advent and use of single-bead antigen assays, more was learned about donor-specific antibodies (DSAs) against these antigens. Interest in these antigens and antibodies grew when cases of acute antibody-mediated rejection (AMR), mixed rejections, chronic AMR, and reduced graft survival were reported with DSAs against these antigens. Although the deleterious effects of these DSAs are more pronounced in retransplants, harmful effects have also been observed in first-time recipients. DSAs against each of these antigens can trigger rejection alone. Their combination with DSAs against HLA-A, HLA-B and HLA-DR can cause more damage. It has been shown that strategies that reduce mismatches for these antigen lead to fewer rejections and better graft survival. There is a need for greater consensus on the universal typing of these antigens prior to transplantation for better patient and graft outcomes. This review focuses on the interaction of these antigens with lymphocytes and killer immunoglobulin receptors, arguments for not typing them, detailed analyses of the literature about their harmful effects, potential strategies moving forward, and recommendations for the future.

• Kidney transplantation
• HLA-C
• HLA-DP
• HLA-DQ
• Donor specific antibodies
• Review

Pre-transplant donor specific antibodies (DSA), directed at non-self human leukocyte antigen (HLA) protein variants present in the donor organ, have been associated with worse outcomes in kidney transplantation. The impact of the mean fluorescence intensity (MFI) and the target HLA antigen of the detected DSA has, however, not been conclusively studied in a large cohort with a complete virtual cross-match (vXM).

We investigated the effect of pre-transplant DSA on the risk of antibody-mediated rejection (ABMR), graft loss, and the rate of eGFR decline in 411 DSA positive transplants and 1804 DSA negative controls.

Pre-transplant DSA were associated with a significantly increased risk of ABMR, graft loss, and accelerated eGFR decline. DSA directed at Class I and Class II HLA antigens were strongly associated with increased risk of ABMR, but only DSA directed at Class II associated with graft loss. DSA MFI markedly affected outcome, and Class II DSA were associated with ABMR already at 500-1000 MFI, whereas Class I DSA did not affect outcome at similar low MFI values. Furthermore, isolated DSA against HLA-DP carried comparable risks for ABMR, accelerated eGFR decline, and graft loss as DSA against HLA-DR.

Our results have important implications for the construction and optimization of vXM algorithms used within organ allocation systems. Our data suggest that both the HLA antigen target of the detected DSA as well as the cumulative MFI should be considered and that different MFI cut-offs could be considered for Class I and Class II directed DSA.

• Antibodies
• Cohort Studies
• Graft Rejection
• Graft Survival
• HLA Antigens
• HLA-DP Antigens
• Humans
• Kidney Transplantation/adverse effects
• Switzerland
• Tissue Donors

• antibody-mediated rejection
• hla alloantibodies
• renal transplantation

• Adult
• Graft Rejection/immunology
• HLA-DP Antigens/immunology
• Humans
• Kidney Transplantation
• Male

• Wellcome Trust
• 081020 Wellcome Trust
• G0900364 Medical Research Council

• hlamatchmaker
• hla
• epitope structure
• histocompatibility
• eplet

• Algorithms
• Computational Biology
• Epitopes/immunology
• HLA-DP Antigens/chemistry
• HLA-DP Antigens/metabolism
• HLA-DQ Antigens/chemistry
• HLA-DQ Antigens/metabolism
• HLA-DR Antigens/chemistry
• HLA-DR Antigens/metabolism
• Histocompatibility Testing/methods
• Humans

• R01 AI055933 NIAID NIH HHS
• AI-55933 NIAID NIH HHS