Low Hydrophobic Mismatch Scores Calculated for HLA-A/B/DR/DQ Loci Improve Kidney Allograft Survival

Abstract

We evaluated the impact of human leukocyte antigen (HLA) disparity (immunogenicity; IM) on long-term kidney allograft survival. The IM was quantified based on physicochemical properties of the polymorphic linear donor/recipient HLA amino acids (the Cambridge algorithm) as a hydrophobic, electrostatic, amino acid mismatch scores (HMS\AMS\EMS) or eplet mismatch (EpMM) load. High-resolution HLA-A/B/DRB1/DQB1 types were imputed to calculate HMS for primary/re-transplant recipients of deceased donor transplants. The multiple Cox regression showed the association of HMS with graft survival and other confounders. The HMS integer 0-10 scale showed the most survival benefit between HMS 0 and 3. The Kaplan-Meier analysis showed that: the HMS=0 group had 18.1-year median graft survival, a 5-year benefit over HMS>0 group; HMS ≤ 3.0 had 16.7-year graft survival, a 3.8-year better than HMS>3.0 group; and, HMS ≤ 7.8 had 14.3-year grafts survival, a 1.8-year improvement over HMS>7.8 group. Stratification based on EMS, AMS or EpMM produced similar results. Additionally, the importance of HLA-DR with/without -DQ IM for graft survival was shown. In our simulation of 1,000 random donor/recipient pairs, 75% with HMS>3.0 were re-matched into HMS ≤ 3.0 and the remaining 25% into HMS≥7.8: after re-matching, the 13.5 years graft survival would increase to 16.3 years. This approach matches donors to recipients with low/medium IM donors thus preventing transplants with high IM donors.

Improving Access to HLA-Matched Kidney Transplants for African American Patients

“…The HaploStats algorithm was used to impute high-resolution HLA-A/B/DRB1/DQB1 types ( 17 , 22 ) based on the frequency distribution in the race ( 23 , 24 ). The accuracy of imputation was confirmed on 1,095 Caucasian transplant candidates at Queen Elizabeth II Health Sciences Centre, Halifax, Canada typed at HLA-A/B/DRB1/DQB1 loci using a combination of sequence based typing and extended region SSO methods ( 13 ); The 1,095 HLA genotypes were used to form 547 simulated donor/recipient pairs. Their serological HLA split antigen data was used to impute the likely high-resolution HLA types, and the two sets of HLA types were compared.…”

“…The imputed 4-digit types were 96% identical for HLA-A, 92% for -B, 73% for -DRB1, and 85% for -DQB1 with the high-resolution types received in laboratory. Furthermore, when the HMS, EMS, AMS were calculated for these 547 donors/recipient pairs using their real high-resolution HLA-types, were compared to the scores calculated using their imputed high-resolution HLA types in paired t-test, no difference was found (p=0.31), see ref ( 13 ).. In addition, comparison of trimmed HMS, EMS and AMS values calculated based on either real or imputed high-resolution types all produced R 2 -values of 0.99 showing little, if any, impact of HLA genotype imputation on the proof-of-concept results ( Supplemental Figure 1 ).…”

“…Estimations of HLA diversity among races demonstrated the low likelihood of providing HLA-matched transplants for both Blacks and patients of other races ( 10 ). However, our recent publication showed that the hydrophobic mismatch score (HMS), based on a continuous HLA amino acid donor/recipient disparity scale, provided a unique opportunity to adjust HMS thresholds ( 13 ). Therefore, we propose replacing the 6-integer A-B-DR analog HLA-based matching ( 14 , 15 ) with a linear HMS scale utilizing race-adjusted thresholds.…”

HLA topography enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients

“…In the context of antiviral responses, it is appreciated that AA polymorphisms contribute to immune focusing and immunodominance. 19 Although various methods have been used to explain why certain HLA residue mismatches may be immunogenic, including hydrophilicity, 74 protrusion, 51 and other physicochemical features, 49,50,75 these approaches have all generally lacked discriminatory power. Indeed, none of these physicochemical features of polymorphic mismatched residues correlated with immunogenicity in our study.…”