Bekbolsynov Dulat, Mierzejewska Beata, Borucka Jadwiga, Liwski Robert S, Greenshields Anna L, Breidenbach Joshua, Gehring Bradley, Leonard-Murali Shravan, Khuder Sadik A, Rees Michael, Green Robert C, Stepkowski Stanislaw M
Department of Medical Microbiology and Immunology, University of Toledo, Toledo, OH, United States.
Parexel International, Warsaw, Poland.
Front Immunol. 2020 Oct 29;11:580752. doi: 10.3389/fimmu.2020.580752. eCollection 2020.
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.
我们评估了人类白细胞抗原（HLA）差异（免疫原性；IM）对长期同种异体肾移植存活的影响。IM根据多态性线性供体/受体HLA氨基酸的物理化学性质（剑桥算法）进行量化，作为疏水、静电、氨基酸错配分数（HMS\AMS\EMS）或表位错配（EpMM）负荷。对已故供体移植的初次/再次移植受者进行高分辨率HLA - A/B/DRB1/DQB1分型推算，以计算HMS。多因素Cox回归分析显示了HMS与移植物存活及其他混杂因素之间的关联。HMS整数0 - 10量表显示，HMS在0至3之间时移植物存活获益最大。Kaplan - Meier分析表明：HMS = 0组的移植物中位存活时间为18.1年，比HMS>0组多5年的获益；HMS≤3.0组的移植物存活时间为16.7年，比HMS>3.0组多3.8年；HMS≤7.8组的移植物存活时间为14.3年，比HMS>7.8组多1.8年。基于EMS、AMS或EpMM进行分层分析产生了相似的结果。此外，还显示了HLA - DR伴或不伴 - DQ IM对移植物存活的重要性。在我们对1000对随机供体/受体的模拟中，75% HMS>3.0的配对重新匹配为HMS≤3.0，其余25%重新匹配为HMS≥7.8：重新匹配后，移植物存活时间将从13.5年增加到16.3年。这种方法将供体与低/中等IM供体的受体进行匹配，从而避免与高IM供体进行移植。
