The quest to decipher HLA immunogenicity: Telling friend from foe

Abstract

| INTRODUC TI ONAdvances in HLA typing and HLA antibody testing over the past two decades transformed our ability to assess donor/recipient compatibility in the context of organ transplantation. Beginning from serologic donor/recipient HLA matching through emphasis on avoidance of preformed donor-specific HLA antibodies (DSAs), current approaches delve into amino acid sequences of HLA alleles, assessing the so-called molecular mismatch between donor and recipient, using one or more of the currently available tools: HLAMatchmaker, [1][2][3][4] Amino-Acid comparison, Electrostatic Mismatch Score (EMS 5-7 ), or PIRCHE-Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA-Class II antigens. 8-10 A short description of each method is provided in the supplemental material.It is notable that only minor variations were found when comparing the ability of these different approaches to predict poor graft outcome (correlation ranging between R 2 of .85-.96). 8,11 In addition, when different patient populations were studied (eg, pediatric vs adult; kidney vs lung), different cutoff values were reported, 12-19 indicating the need Funding information Paul I Terasaki Research FoundationMolecular mismatch load analysis was recently introduced as a means for performing risk stratification following organ transplantation. However, although good correlation was demonstrated between molecular mismatch load and generation of de novo donor-specific HLA antibody (DSA), quite a few exceptions exist, and the underlying factors that define HLA immunogenicity remain unclear. Herein, we present a new paradigm to interrogate differences between molecular mismatches that lead to the generation of de novo DSA and those that do not (the 2MM1DSA cohort).Specifically, patients transplanted across 2 HLA-DQ mismatches, who formed de novo DSA only to one mismatch (foe) but not the other (friend), provide a unique environment in which patient-specific factors that affect the immune response other than immunogenicity, such as infection and immunosuppression, can be controlled for. It further permits focusing on mismatches uniquely exhibited by the de novo DSA allele, rather than mismatches shared by both DSA and non-DSA alleles. This concept paper illustrates several examples, highlights the need for center-specific or population-specific cutoff values for posttransplant risk stratification, and mostly argues that if there is no direct correlation between molecular mismatch load and immunogenicity, then molecular mismatch load must not be adopted as an approach for equitable organ allocation. K E Y W O R D Salloantibody, antigen presentation/recognition, clinical research/practice, histocompatibility, organ allocation

Development of an immunogenicity score for HLA‐DQ eplets: A conceptual study

“…25 As shown by Kramer et al as well as Tambur et al, the current eplet lists need further refinements and verification. 18,21 Our data may also help in this regard. If confirmed in other studies, not reacting eplets might be removed from the eplet lists.…”

Substituting imputation of HLA antigens for high-resolution HLA typing: Evaluation of a multiethnic population and implications for clinical decision making in transplantation

“…Overall, the imputed HLA type 37% of individuals contained at least TA B L E 3 Frequency of accurate imputation of high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 alleles when entering low-resolution HLA-A, -B, and -DR typing in HaploStats, overall and subgrouped by self-reported race/ ethnicity HaploStats HLA-A, -B, -DR to -A, -B, -C, -DRB1, -DQB1 TA B L E 4 Frequency of accurate imputation of high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 alleles when entering low-resolution HLA-A, -B, -C,-DR, and -DQ in HaploStats, overall and subgrouped by self-reported race/ ethnicity HLA-A, -B, -C, -DRB1, -DQB1 DQ antigen with the lower eplet mismatch load without developing antibody against the DQ antigen with the higher mismatch load. 18 Moreover, there are numerous examples in which the recipient developed de novo HLA-DSA despite the fact that the donor exhibited only a single amino-acid mismatch. 19 Our study benefited from including a large number of non-Caucasian patients, in whom previous information on HLA imputation is limited.…”

Sensitization in transplantation: Assessment of risk (STAR) 2019 Working Group Meeting Report

“…Although a strong correlation exists between increased mMM and de novo DSA, some of the patients do develop de novo DSA despite having a low HLA mMM score 101,103 . This emphasizes that certain mMM may have a higher immunogenic impact compared with other mMM and that not all mMM should be assigned the same immunogenic value.…”

“…Based on this body of work, the FDA Center for Drug Evaluation and Research agreed to evaluate the potential role of HLA‐DR/DQ eplet mMM score as a strategy for enrichment or risk stratification in phase 2 and 3 kidney transplant clinical drug development trials and as a prognostic biomarker for de novo DSA, graft rejection, and graft failure 99 . Whether eplet mMM or single molecule HLA‐DR or ‐DQ eplet mMM scores can be used to guide risk stratification for personalized immunosuppression requires proof through prospective clinical trials, because different investigators report different risk thresholds 100‐103 …”