Can We Use Eplets (or Molecular) Mismatch Load Analysis to Improve Organ Allocation? The Hope and the Hype

Abstract

In recent years, there have been calls for implementation of "epitope matching" in deceased-donor organ allocation policies (later changed to "eplet matching"). Emerging data indeed support the use of molecular mismatch load analysis in specific patient groups, with the objective of posttransplant stratification into different treatment arms. For this purpose, the expectation is to statistically categorize patients as low-or high-immune-risk. Importantly, these patients will continue to be monitored‚ and their risk category, as well as their management, can be adjusted according to on-going findings. However, when discussing deceased donor organ allocation and matching algorithms, where the decision is not modifiable and has lasting impact on outcomes, the situation is fundamentally different. The goal of changing allocation schemes is to achieve the best possible HLA compatibility between donor and recipient. Immunologically speaking, this is a very different objective. For this purpose, the specific interplay of immunogenicity between the donor and any potential recipient must be understood. In seeking compatibility, the aim is not to redefine matching but to identify those mismatches that are "permissible" or‚ in other words, less immunogenic. In our eagerness to improve transplant outcome, unfortunately, we have conflated the hype with the hope. Terminology is used improperly, and new terms are created in the process with no sufficient support. Here, we call for a cautious evaluation of baseline assumptions and a critical review of the evidence to minimize unintended consequences.

Public values and guiding principles for implementing epitope compatibility in kidney transplantation allocation criteria: results from a Canadian online public deliberation

“…This may be especially important with epitope compatibility – a novel, cutting-edge technique that would impact the kidney offer order and waiting time. Again, the fact that clinical evidence for epitope compatibility is evolving [ 6 , 29 – 32 ] – which raised concern for members of the deliberation who value Evidence-based Healthcare—heightens the need for Accountability to ensure that new policies perform as projected and result in benefit for transplant recipients and society more broadly.…”

Assessing the allogenic realness of the Cw1/12/15 pattern occurring in the LABScreen single antigen assay

“…Indeed, a recent report clearly showed that a majority of the so‐called “antibody‐verified” eplets that is, those present on the cell surface of normal cells, which define the authentic targets of allogenic Abs with clinical relevance, has not been sufficiently well defined experimentally 24 . A recent review article also warned about the use of Epregistry to define eplet matching for organ allocation 25 . A combination of approaches such as the one we designed for the Cw1/12/15 pattern would largely facilitate the establishment of an accurate registry.…”

“…24 A recent review article also warned about the use of Epregistry to define eplet matching for organ allocation. 25 A combination of approaches such as the one we designed for the Cw1/12/15 pattern would largely facilitate the establishment of an accurate registry. Moreover, this is a very useful approach in order to precisely define new eplets, beyond the mere ability to demonstrate the capacity of an antibody to bind a donor antigen or allele.…”

DQA1 Eplet Mismatch Load As an Independent Risk Factor of CLAD After Lung Transplantation

“…14 Potentially, Ep MM load could be considered as a selection criterion before lung transplantation and for risk stratification posttransplantation, the same way it is already used in the case of kidney transplants. 15 The first evidence for the independent impact of HLA-DRB1/3/4/5+DQA/B Ep MM in CLAD was observed several years ago. 16 Subsequent studies demonstrated that HLA class-II Ep MM were able to predict de novo HLA class-II donor specific antibodies (DSAs).…”

“…14 Potentially, Ep MM load could be considered as a selection criterion before lung transplantation and for risk stratification posttransplantation, the same way it is already used in the case of kidney transplants. 15 The first evidence for Background. Lung transplantation remains the treatment of choice for end-stage lung diseases, and recipient selection is currently based on clinical urgency, ABO compatibility, and donor size.…”