Received: 16 November 2020 | Revised: 12 December 2020 | Accepted: 20 December 2020

DOI: 10.1111/iji.12525

INVITED REVIEW

Matchmaker, matchmaker make me a match: Opportunities

and challenges in optimizing compatibility of HLA eplets in
transplantation

William Lemieux1 | Hossein Mohammadhassanzadeh1 | William Klement1,2 |

Claude Daniel3 | Ruth Sapir-Pichhadze1,4,5

1
Centre for Outcomes Research and
Evaluation (CORE), Research Institute of Abstract
McGill University Health Centre, Montréal, The development of donor-specific antibodies (DSAs) is a major complication in
QC, Canada
2 transplantation, which is associated with inferior graft survival, impaired quality of
Canadian Blood Services, Ottawa, Ontario,
Canada life, and increased healthcare costs. DSA develop upon recognition of nonself HLA
3
Division of Hematology, McGill University by the recipient's immune system. HLA molecules contain epitopes, which are the
Health Centre, Montréal, QC, Canada
4
surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an
Division of Nephrology and the Multi-
Organ Transplant Program, Royal Victoria algorithm for assessing donor:recipient HLA compatibility at the level of structurally
Hospital, McGill University Health Centre, defined HLA targets called eplets. The consideration of eplets, rather than the whole
Montréal, QC, Canada
5 HLA molecule, could offer some advantages when classifying the immune risk associ-
Department of Epidemiology, Biostatistics
and Occupational Health, McGill University, ated with particular donor:recipient pairs. Assessing compatibility at the level of HLA
Montréal, QC, Canada
eplets could decrease misclassification of post-transplant immune risk by improving
Correspondence specificity, when antibodies are confirmed to be directed against donor eplets miss-
Ruth Sapir-Pichhadze, Centre for Outcomes
ing from the recipient's repertoire of eplets. Consideration of eplets may also increase
Research and Evaluation (CORE), McGill
University Health Centre, Montréal, QC, the sensitivity of immune risk assessment, when identifying mismatched eplets that
Canada.
could give rise to new, not previously detected, donor-specific antibodies post-trans-
Email: ruth.sapir-pichhadze@mcgill.ca
plant. Eplet matching can serve as a rational strategy for immune risk mitigation.
Funding information
Herein, we review the evolution of HLA (in) compatibility assessment for organ al-
Fonds de Recherche du Québec - Santé,
Grant/Award Number: chercheur boursier location. We outline challenges in the implementation of eplet-based donor:recipient
clinician award (254386); Génome Québec,
matching, including unavailability of allele-level donor genotypes for 11 HLA loci at
Grant/Award Number: Precision Medicine
CanPREVENT AMR the time of organ allocation and difficulty in assessing the hierarchy of immune risk
associated with particular HLA eplet mismatches. Opportunities to address some of
the current shortcomings of donor genotyping and HLAMatchmaker are also dis-
cussed. While there is a demonstrated benefit in the application of HLAMatchmaker
for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping
methods, compilation of large data sets with allele-level genotypes, and standardiza-
tion of methods to verify eplets as determinants of immune-mediated injuries are
required before HLA eplet matching is implemented in organ allocation to improve
upon transplant outcomes.

Int J Immunogenet. 2021;48:135–144. wileyonlinelibrary.com/journal/iji© 2021 John Wiley & Sons Ltd | 135
136 | LEMIEUX et al.
KEYWORDS
allograft, histocompatibility, immune response, immunology, matching, transplantation, typing
1 | I NTRO D U C TI O N
Currently, the assessment of donors and candidates’ compatibil-
ity relies on acceptable mismatch strategies, with unacceptable
mismatches defined by the presence of preformed donor-specific
antibodies (DSAs) targeting human leucocyte antigens (HLAs). Anti-
HLA antibodies are produced in response to previous exposure to
HLA through blood transfusions, pregnancy and transplantation.
While the verification of preformed antibodies relied historically on
cell-dependent crossmatches, nowadays donor:recipient compatibil-
ity is assessed by virtual crossmatch or flow cytometry crossmatch
(Tait, 2016; Tinckam, 2009). Complement-dependent cytotoxicity
(CDC) assays inform the highest risk of immune-mediated injuries.
On the other hand, flow cytometry and virtual crossmatches are
considered more sensitive assays, allowing detection of lower titre
and noncomplement-binding DSAs that pose a lower immune risk
than that identified by positive CDC. In contrast to flow cytome-
try and CDC, virtual crossmatches rely on knowledge of donor HLA
genotype and are deemed positive when single antigen bead (SAB)
assays confirm presence of DSA (Tait, 2016; Tambur et al., 2020;
Tinckam, 2009).
2 | PA N E L R E AC TI V E A NTI B O D I E S A N D
O PP O RT U N ITI E S FO R CO N S I D E R ATI O N O F
H L A E PITO PE S
The implementation of virtual crossmatch is based on the verifica-
tion of panel reactive antibodies (PRAs). The PRA offers a score from
zero to 100% to represent the proportion of the donor pool a given
transplant candidate may have antibodies against. To determine the
PRA score, transplant candidates undergo routine screening by SAB
assays. This is often referred to as a calculated PRA (cPRA), which
considers the entire donor population rather than a select panel of
representative donors as in the case of cell-based PRA (Tinckam
et al., 2015). The introduction of cPRA served to limit the variabil-
ity observed when relying on different cell-based panels (Kransdorf
et al., 2017). Moreover, anti-HLA antibody screening in candidates
and the calculation of PRA have improved the capability to predict
cellular crossmatch results and, consequently, have resulted in a de-
creased likelihood of transplantation in the presence of unaccepta-
ble HLA mismatches, rejection and graft failure (Cherikh et al., 2006;
Morris et al., 2019; Roll et al., 2020; Tinckam, 2009).
Despite the advantages of cPRA and the virtual crossmatch,
some limitations must be noted. First, cPRA may be highly depen-
dent on the timing and context of the testing performed. Anti-HLA
antibodies may wax and wane over time, resulting in a fluctuating
repertoire of unacceptable mismatches and, consequently, also re-
sulting in different proportions of potentially compatible donors
from the pool. Acknowledging this, transplant centres may use the
cumulative cPRA, which considers anti-HLA antibodies that have
been detected over the entire course of pre-transplant screening
(Beausang et al., 2017; Tinckam et al., 2015). The cumulative cPRA
is also dependent on the detection of antibodies, which is itself de-
pendent on laboratory practices. This dependency makes standard-
ization of SAB assay analysis challenging (Reed et al., 2013). Factors,
including serum handling, choice of mean fluorescence intensity
(MFI) threshold to determine the presence of anti-HLA antibody,
and the specific test kit used, are critical to the final interpretation
of the assay (Konvalinka & Tinckam, 2015). Further complicating the
interpretation of SAB assays, is their sensitivity to issues intrinsic to
the serum sample, such as inhibitory substances (referred to as the
‘prozone’ effect) and bead saturation (Konvalinka & Tinckam, 2015;
Tambur et al., 2020; Tambur & Wiebe, 2018). Thus, the virtual cross-
match is vulnerable to misclassification of candidates’ risk of recall
responses due to immune memory, which may yield diverse reper-
toires of unacceptable mismatches.
While cPRA is informed by existing (and/or historic) anti-HLA
antibodies, it fails to capture the risk of developing new, previously
unobserved, antibodies against donor HLA. When detected for the
first-time post-transplant, these antibodies are referred to as de
novo DSAs. Epitope analysis could overcome some of the limitations
of cPRA as a determinant of historic, current and potentially de novo
DSA (Duquesnoy, 2001; Terasaki et al., 1989). The focus of epitope
analysis is on specific polymorphic regions on the HLA that can bind
to antibodies. The availability of a panel of monoclonal anti-HLA
antibodies has helped grow the understanding of the concept of
epitopes (Tambur & Claas, 2015). Some epitopes may be restricted
to target a specific HLA protein, but others are shared between
different proteins, with each allele coding for HLA protein and the
unique combination of epitopes associated with it. Epitopes that are
common to different HLA molecules explain how certain anti-HLA
antibodies may demonstrate cross-reactivity to proteins coded by
different alleles. Immunogenetics allow the recognition of epitope
repertoire from the HLA genotype.
Structural analysis of crystalized HLA complexes allowed the
identification of accessible amino acids on HLA molecules that
can be bound by antibodies (Duquesnoy, 2001; Gu et al., 2019).
Based on this principle, Duquesnoy and colleagues developed
HLAMatchmaker, a structurally based matching program. Each HLA
antigen was viewed as a string of eplets or short sequences involving
polymorphic amino acid residues in antibody-accessible positions.
Initially, HLAMatchmaker determined which triplets, linear se-
quences of three amino acid residues, were different between donor
and recipient (Duquesnoy, 2001). In subsequent iterations of the al-
gorithm, a revised concept of eplets was defined (Duquesnoy, 2006).
This concept arose from the observation that, in addition to a func-
tional epitope, which includes about 2–5 residues that dominate the
LEMIEUX et al.
strength and specificity of binding with antibodies, HLA antigens
also have structural epitopes consisting of 15–22 residues that pro-
vide supplementary interactions that increase the stability of the
antigen–antibody complex. Different from triplets, eplets did not as-
sume sequentially contiguous amino acids but rather structurally de-
fined amino acid polymorphisms within proximity in the context of
each protein's 3D configuration. As a result, many (but not all) eplets
were also triplets. This updated definition (in the form of eplets) is
considered a more accurate representation of the constituents of
functional epitopes.
A comparison between the donor's repertoire of eplets with
that of the recipient's allows for the estimation of the cumula-
tive mismatch load, or the sum of eplet mismatches, by HLA locus
and/or class. To document the evolving appreciation of eplets and
their validation as epitopes through antibody verification, the HLA
Epitope Registry (https://www.epreg​istry.com.br/) was established
(Duquesnoy et al., 2018). The HLA Epitope Registry captures lists of
alleles associated with each eplet, provides data on whether a puta-
tive eplet has associated antibody reactivity (indicating that it may
be an immunologically recognized epitope) and outlines the valida-
tion method used for antibody testing.
As the biologically rational measure for donor:recipient HLA
compatibility assessment, consideration of HLA eplets could min-
imize the misclassification of transplant candidate's immune risk.
Further, eplet analysis offers a comprehensive and ‘static’ assessment
of HLA (in)compatibility, independent of time and MFI threshold for
detecting HLA antibodies. To date, however, the assessment of eplet
compatibility by the HLAMatchmaker algorithm has relied on the
cumulative eplet mismatch load (Lim et al., 2018; Sapir-Pichhadze
et al., 2015; Wiebe et al., 2013). While eplet mismatch load has been
shown to be associated with inferior transplant outcomes, optimiz-
ing epitope compatibility at the time of organ allocation requires
consideration of risk informed by the immunogenicity and antigenic-
ity of individual eplet mismatches.
3 | A S S E S S I N G I N CO M PATI B I LIT Y AT TH E
LE V E L O F H L A E PLE T S
3.1 | Applications in highly sensitized patients
A consideration of HLA eplet-based donor and recipient compat-
ibility has been implemented by the Eurotransplant program to
identify compatible donors for highly sensitized patients. In this
context, patients with a PRA > 6% are deemed sensitized and
patients with PRA > 85% are deemed highly sensitized as they
express anti-HLA antibodies against more than 85% of the popu-
lation (Heidt et al., 2015). Highly sensitized patients are less likely
to access transplantation and be matched with a compatible donor
(Sebastiaan Heidt & Claas, 2018; Smits et al., 1998). Many groups
recognized the need to address the scarcity of donors available for
highly sensitized patients and especially patients with a PRA nearing
100% who would require exceedingly large donor pools to have a
| 137
reasonable chance of finding a suitable donor (Keith & Vranic, 2016).
This can translate to extended wait times for transplantation. To in-
crease access to transplantation for the above disadvantaged popu-
lation, Eurotransplant developed the Acceptable Mismatch (AM)
program (Claas et al., 1988) that allowed mismatches in HLA-A or
HLA-B when DSAs were not present against the donor HLA pro-
teins as determined by cell-based crossmatching (Heidt et al., 2015).
Noninherited maternal antigens were also considered acceptable
in the AM program, as tolerance of these HLA is supposed to be
acquired during foetal development (Claas et al., 1988). To further
expand the donor pool, mismatches were also allowed at other HLA
loci, while simultaneously ensuring a negative crossmatch result
(Claas & Doxiadis, 2009). Advances in immunogenetics have allowed
an increased understanding of amino acid variations and their role
in DSA development. This was followed by an evolution of the AM
program to consider transplantation in the presence of 0–2 triplet
mismatches (Heidt et al., 2015).
The consideration of epitope compatibility in highly sensitized
patients has the potential to increase the specificity with which
donors are classified as incompatible (Figure 1, Highly Sensitized).
Practically, in addition to transplantation occurring on the rare occa-
sions when HLA allele-compatible donor is identified, this strategy
also enables organ allocation to highly sensitized patients despite
presence of mismatched HLA alleles, provided that the associated
repertoire of eplets is compatible: as more allele combinations are
deemed compatible, this inevitably helps expand the donor pool.
Indeed, it has been shown that matching at the eplet level (rather
than the antigen level) allows for a higher probability of identify-
ing compatible donors for highly sensitized patients (Duquesnoy
et al., 2003). By drawing parallels from Eurotransplant's AM program
and comparing to the current allocation strategy used in Australia,
Nguyen et al. were also able to determine that eplet matching was
beneficial for the highly sensitized patients, without being a bur-
den and/or compromising access to transplantation on the part of
nonhighly sensitized transplant candidates (Nguyen et al., 2014).
Importantly, the AM program was shown to decrease rejection rates
in AM patients and unsensitized individuals (Heidt et al., 2019).
3.2 | Applications across transplant candidate
populations
In addition to increased access to transplantation in highly sensitized
patients, the assessment of eplet compatibility may offer advantages
across transplant candidates whether sensitized or not. The advan-
tage of this strategy can be attributed to its ability to explain (and help
avoid) not only preformed antibodies but also de novo DSA (Figure 1,
PRA 0% and PRA > 0%). A perfect donor:recipient HLA allele match-
ing may be clinically impractical in the presence of over 27,000 HLA
alleles across 11 HLA genes. In contrast, by virtue of a smaller number
of potential eplets which may be common to different HLA alleles of
the same locus or across loci, accomplishing compatibility at the level
of the eplet is expected to be more feasible. When perfect matching
138 | LEMIEUX et al.

F I G U R E 1 Qualitative representation of the impact of transitioning from calculated panel reactive antigens (cPRA) to eplet-based cPRA
on assessment of immune risk. Assessing compatibility at the level of HLA epitopes could decrease misclassification of post-transplant
immune risk by improving specificity (when antibodies detected are linked to eplets missing from the recipient's repertoire) and sensitivity
(when identifying mismatched eplets that could give rise to immune-mediated injuries even in the absence of preformed antibodies). Specific
eplet mismatches may inform variable degrees of risk and this may be further modified given the role of T cells in the alloimmune response
as well as the recipient's HLA type [Colour figure can be viewed at wileyonlinelibrary.com]

is not possible to achieve, assessing (in)compatibility at the level of
HLA eplets can be used for risk stratification. Indeed, eplet mismatch
load has been linked to the development of de novo DSA, T-cell medi-
ated rejection, transplant glomerulopathy and graft failure (Hamada
et al., 2020; Sapir-Pichhadze et al., 2015; Sapir-Pichhadze et al., 2020;
Senev, Coemans, et al., 2020; Wiebe et al., 2019). While many studies
focus on kidney transplantation, the link between eplet (in)compat-
ibility and patient outcomes remains consistent in the context of other
solid organ transplants (Hamada et al., 2020; McCaughan et al., 2018;
Walton et al., 2016). Importantly, a better understanding of immune
risk associated with eplet incompatibility can inform surveillance
schedules and personalized immunosuppression regimens in both
adult and paediatric patients (Sharma et al., 2020; Wiebe et al., 2015;
Wiebe & Nickerson, 2020; Wiebe et al., 2017).
4 | ROA D M A P TO I M PLE M E NTATI O N
O F E PLE T M ATC H I N G — C H A LLE N G E S A N D
O PP O RT U N ITI E S
4.1 | Measured and imputed HLA Genotypes
The first step towards implementing eplet matching relies on the
availability of allele-level HLA genotyping (Figure 2). Genotyping
at all 11 loci of HLA genes (Class I (A, B, C) and Class II (DRB1,
DRB3/4/5, DQA1/B1, DPA1/B1)) is necessary to determine the
candidate's and donor's eplet repertoire. HLA genotyping methods
can be classified into two broad categories: probe-based meth-
ods and sequence-based methods. Probe-based methods include
sequence-specific primer (SSP) typing and sequence-specific oli-
gonucleotide probe typing (SSO). These two techniques offer low-
cost rapid turnaround typing (Smith et al., 2019). Yet, both methods
have the disadvantage of providing low or, at best, intermediate
resolution genotyping, with residual ambiguity of allele assign-
ment. Of these two, SSO typing is more common in clinical prac-
tice as it can increase efficiency through batching multiple samples
(Smith et al., 2019).
In contrast, in sequence-based genotyping, the specific allele
is determined by resolving the exact genomic sequence of alleles.
Sanger sequencing is often referred to as sequence-based typing
(SBT) that enables high-resolution typing of HLA alleles. Next-
generation sequencing (NGS) has reduced the infrequent inaccura-
cies observed in SBT but is associated with higher implementation
costs, which can be a barrier to its integration in HLA typing labo-
ratories. Moreover, NGS is not immune to residual ambiguity with
occasional allele dropouts (Klasberg et al., 2019). The processing
time required by SBT and NGS methods makes them less useful for
deceased donor genotyping. Therefore, imputation of allele-level
LEMIEUX et al.
F I G U R E 2 Challenges and opportunities on path to incorporating HLA eplet compatibility in immune risk assessment and organ
allocation. Abbreviations: SAB, single antigen bead assay [Colour figure can be viewed at wileyonlinelibrary.com]
genotypes is often used for clinical decision making and for analysis
of large legacy data sets.
Imputation of allele-level genotypes from low or intermediate
resolution typing has been utilized to overcome HLA allele ambigu-
ity. The imputation process relies on probabilistic inference, which
considers population-level allele and haplotype frequencies. Recent
studies have shown that imputations may result in inaccuracies in
allele and, consequently, in eplet assignments (D'Souza et al., 2018;
Engen et al., 2020; Senev, Emonds, et al., 2020). The inaccuracies
were more pronounced when applied to HLA class II and among pa-
tients of non-Caucasian self-reported ancestry. As with any tool that
is being used for research or clinical purposes, it is of paramount
importance to be familiar with its advantages and limitations in order
to apply the tool responsibly. Imputation accuracy is expected to im-
prove when 2-field allele and haplotype frequencies are available
for the population considered and by providing the imputation tool
the most detailed genotyping information possible (e.g. intermediate
resolution typing with NMDP ambiguity codes for 11 HLA loci).
With advances in genotyping technologies, it is expected that
sequencing-based typing could be implemented with shorter turn-
around times or that an epitope-based typing strategy could be de-
veloped. This could allow for the use of eplet matching for organ
allocation without imputation. Importantly, a novel approach has
been designed using long-read nanopore sequencing (LNS). While
the long reads minimize inaccuracies introduced when assembling
short sequencing reads, this technique still suffers from some short-
comings in read analysis and interpretation (Matern et al., 2020).
Should these deficiencies be resolved, the turnaround time of LNS
| 139
would allow the rapid generation of high-resolution typing in a mat-
ter of hours as required in the deceased donor transplant context
(Liu, 2020). Indeed recently, Mosbruger et al. reported on the appli-
cation of nanopore sequencing technology for the rapid (<6 hr) and
comprehensive characterization of 11 HLA loci increasing the likeli-
hood that this technology will be implemented in clinical practice to
improve donor:recipient compatibility (Mosbruger et al., 2020).
4.2 | The issue of rare and null HLA alleles
Apart from allele ambiguity, when relying on probe-based (and
even sequence-based) methods to assign allele-level genotypes, the
eplet repertoire assignment may be limited in the case of rare al-
leles. An algorithm can be trained to automate and accelerate the
incorporation of rare alleles, which are currently not represented in
the HLAMatchmaker algorithm or the HLA Epitope Registry. This
algorithm will identify nucleotide sequences that encode the same
protein sequences for the peptide binding domains (exon 2 and exon
3 for HLA class I and exon 2 for HLA class II alleles) as the more com-
mon and well-documented alleles. Over time, the algorithm would
also be able to identify new polymorphic DNA sequences that can
code for antibody targets with physiochemical properties within 3D
HLA molecules that are likely to represent epitopes.
Another limitation of the current HLAMatchmaker algorithm is
the way it handles null alleles (Elsner & Blasczyk, 2004). Null alleles
are characterized by a lack of a serologically detectable product.
While they should not represent a major issue, it is important to
140 | LEMIEUX et al.
acknowledge the existence of alleles with various degrees of ex-
pression in transplantation and how they may contribute to over-
estimation (e.g. when donors have HLA proteins with null (N) or low
(L) expression) or underestimation (e.g. when recipients have HLA
proteins with null (N) or low (L) expression) of donor:recipient HLA
eplet incompatibility (Elsner & Blasczyk, 2004). Currently, users of
the Excel version of HLAMatchmaker are instructed to maintain
an ‘x’ (indicating no allele present) in the appropriate field for a null
allele. This ensures that null alleles will not be counted as present.
Future updates of HLAMatchmaker should allow direct entry of null
alleles in their standard nomenclature format.
4.3 | Re-exposure to eplets and memory response
Eplet incompatibility predicts the potential for immune-mediated in-
juries, and efforts are underway to identify the most immunogenic
eplets (Hönger et al., 2020). Risk of immune-mediated injuries may
be accentuated with re-exposure to similar HLA eplets. The cur-
rent HLAMatchmaker algorithm does not consider prior sensitiz-
ing events and shared eplets between prior and current allografts.
Patient sensitization after transfusions and prior pregnancies are
even harder to account for when considering HLA eplet compatibil-
ity. Candidates for re-transplantation or those with prior exposure
to eplets consistent with those of the new donor (e.g. because of
pregnancy) may experience a memory response and immune injury.
Even in the absence of preformed DSA, avoiding repeated exposure
to mismatched eplets encountered with a prior donor could help re-
duce risk. Similarly, recognizing nonimmunogenic eplets, which are
unlikely to induce an antibody response and, thus, do not present a
problem upon re-exposure, is also important. While applying a grow-
ing number of restrictions at the time of organ allocation may affect
access to transplantation, mitigating the risk of immune-mediated
injury may facilitate the expansion of the existing donor pool by
virtue of decreasing the number of candidates likely to require re-
transplantation after a premature graft failure. In addition to popula-
tion-based policies, analysis of risk versus benefit must consider the
context and preferences of the individual waitlisted patient.
4.4 | Software for assessing HLA eplet compatibility
The growing popularity of the concept of HLA eplet compatibility
gave rise to the development of several software packages. Tassone
et al conducted eplet analysis of the same donor:recipient pairs by
the HLAMatchmaker program (v2.1) and OLI Fusion MatchMaker
(v4.2) software. The different types of software used yielded dif-
ferent total eplet mismatch loads, inconsistent eplet mismatch
repertoires, and variable antibody verification status (Tassone
et al., 2020). At times, certain software also incorrectly assigned
eplets to HLA alleles. As our understanding of eplets improves, the
HLA Epitope Registry as well as Fusion and HLAMatchmaker un-
dergo intermittent updates (at the time this manuscript was written,
Fusion v4.4 and HLAMatchmaker v3.1 were also available). It is im-
portant to ensure that as our knowledge on clinically relevant eplet
repertoires evolves, changes are applied across all available software
packages consistently.
4.5 | Steps towards verification of eplets
as epitopes
Although the analysis of eplet (in)compatibility enables risk strati-
fication, it is essential to define the repertoire of eplets that must
be prioritized for matching. One must acknowledge that on the one
hand, incompatibility of high-risk eplets, even in the absence of pre-
formed HLA antibodies, can give rise to immune-mediated injuries.
On the other hand, efforts to secure donor:recipient compatibility
on clinically irrelevant or low-risk eplets may unjustifiably delay ac-
cess to transplantation in certain individuals. Promoting eplet-based
organ allocation requires the verification of individual eplet mis-
matches as biomarkers predictive of immune-mediated injury.
To record clinically relevant eplets, Duquesnoy and collaborators
have initiated a process to document and track antibody-verified
epitopes on the HLA Epitope Registry. However, the experimental
validation of each eplet in the registry varies; it includes verification
by human monoclonal antibodies, elution/absorption, mouse mono-
clonal antibodies, and sera from multiparous women. Additionally,
the opportunity for antibody verification may be limited because
of additional factors such as the collection of serum, choice of sol-
id-phase assay kit for antibody detection, the repertoire and integrity
of epitopes represented on the assay, MFI threshold used to assign
positive/negative antibody status, strategies for serum handling and
antibody verification. There is a need for clarity and standardization
of experimental procedures required for epitope validation within
laboratories and across transplant centres. Moreover, considering
the dynamic nature of some anti-HLA antibodies, it is also important
to study the impact of eplet mismatches on other clinical outcomes.
Such outcomes may include graft dysfunction, rejection and failure.
Further insights are also needed on how to prioritize compatibil-
ity on specific eplets. For this purpose, one must estimate the weight
each eplet may carry (and in reference to other eplets) in predicting
immune risk when mismatched. Establishing whether some eplets,
by virtue of their inherent properties or due to their combination
with other specific eplets, could be associated with an increased risk
of immune injuries is an important step towards considering eplet
compatibility in organ allocation.
Eplet mismatches may vary in their tendency to trigger an im-
mune response. Varied immunogenicity may be determined by the
physiochemical properties of polymorphic amino acid sequences,
recipient HLA, and the presence or absence of accompanying
T-helper cell epitopes. Kosmoliapsis et al outlined a strategy to de-
termine immunogenicity of HLA by comparing the physiochemical
properties of HLA proteins expressed in donors versus recipients
(Kosmoliaptsis et al., 2009, 2011). The immunogenicity algorithm
developed by Kosmoliapsis and colleagues informs the likelihood
LEMIEUX et al.
of observing an alloantibody response by considering, in addition
to the number of amino acid mismatches, the hydrophobicity and
electrostatic mismatch scores. This topic has also been reviewed in
Ref. Tambur (2018).
It is also important to acknowledge the role of T-helper cell epi-
+
topes in immunogenicity. CD4 T-helper cells are important for the
development of a productive antibody response. After recognition
by the B-cell receptor, HLA can be internalized and degraded into
peptides. These peptides may then be presented on self HLA class
II on B cells. Presentation of self or nonself allo-HLA-derived pep-
tides by recipient's class II HLA may determine whether a specific
eplet mismatch will lead to an antibody response and whether a DSA
isotype switch would occur from IgM to IgG (Dankers et al., 2004;
Kramer et al., 2017, 2019). Algorithms have been developed to con-
sider Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II)
binding to HLA class II (Otten et al., 2013). These represent antigens
from donor HLA class I that can bind to the donor's class II HLA and
can lead to T-helper cell responses. PIRCHE-II is associated with an
increased risk of DSA development, rejection and graft loss (Hamada
et al., 2020; Meszaros et al., 2020; Zheng et al., 2019).
As all mismatches do not seem to have equivalent impact on risk
of immune-mediated injury, it is critical to elucidate the respective
importance of particular eplets to prioritize matching accordingly.
Efforts to establish relative immunogenicity of eplets have been put
forth by establishing the relative frequency of DSA against HLA-DQ
in the context of pregnancy, where mothers have up to 1 HLA-DQ
allele difference in reference to babies (Schawalder et al., 2020).
With a similar objective, Tambur et al. conceived the 2MM1DSA par-
adigm. Planning to study a cohort of patients transplanted across
2 HLA-DQ mismatches and formed de novo DSA to one mismatch
(referred to as foe) but not the other (friend), the team plans to focus
on mismatches exhibited by the allele informing the de novo DSA
development (Tambur et al., 2019). In addition to immunogenicity
represented by DSA development, there is a need to study how
specific class I and class II eplet mismatch may affect hard clinical
endpoints like graft survival at the population level. Distinguishing
between eplets associating with an increased risk versus those that
do not can determine lower risk eplets representing acceptable
mismatches. This knowledge is bound to increase the feasibility of
matching at the eplet level.
4.6 | Informing feasibility of eplet matching
The feasibility of matching at the level of the eplet can be estimated
as the sum of the products of the probabilities of observing com-
binations of HLA haplotypes giving rise to the recipient's complete
eplet repertoire. To avoid unnecessary stringency in access to trans-
plantation, efforts may also focus on a smaller subset of higher risk
eplets. To establish the risk of transplant outcomes as a function of
particular eplet mismatches, analyses should disentangle simultane-
ously observed eplet mismatch profiles informed by the donor's and
recipient's repertoires of eplets.
| 141
Traditionally, health-related information presents challenges
attributed to the collection, incompleteness, sparsity and limited
sample size of medical data. While statistical methods struggle with
data representativeness, skewness of distributions and low signal-
to-noise ratio, machine learning methods spare no effort in counter-
ing the detrimental effect of such limitations. The advent of genomic
data, including NGS data, intensifies the complexity of data analysis
due to substantial increases in dimensionality, greater variations be-
tween patients and greater variations in patients’ response to vari-
ous treatments (Lee & Yoon, 2017). In the context of transplantation,
these variations become more crucial because they are multiplied
and amplified by the number of permutations of possible HLA loci,
alleles and eplets observed in donors and recipients, notwithstand-
ing the variations in the response to immunosuppressant therapies.
Methods of optimizing matching, allocation or management of trans-
plants need to address all these challenges systematically to ensure
that the outcome of an individual patient is optimized while at the
same time benefiting the entire candidate population given the avail-
able donor pool.
There is a need to balance the risks of immune-mediated injuries
with the probability of finding a suitable donor to avoid unnecessary
protraction of waiting time to transplantation. While decision-mak-
ers should be aware of the trade-offs involved, in parallel, the direc-
tives and procedures for organ allocation should concur with views,
values and preferences of the public. Strategies to ensure equity in
access to transplantation when considering patients’ ancestry and
immune risk require careful deliberation. After the implementation
of policies, an additional discussion may be needed with patients
themselves as to their degree of risk they are willing to accept in
general given current organ allocation schemes and at a time spe-
cific organ offers are put forth. Inevitably, such decisions will include
but will not be limited to eplet compatibility as additional donor and
transplant characteristics may inform long-term outcomes in partic-
ular patient subgroups.
5 | CO N C LU S I O N
In conclusion, eplet matching represents an important refinement
of HLA compatibility assessment in organ transplantation with a
potential to mitigate immune-mediated injuries and prolong graft
survival. This review brought to notice some of the challenges on
path to ensuring eplet compatibility at the time of organ allocation,
including the current impracticality of timely high-resolution donor
11-loci HLA typing, the fact that the repertoire of antibody-verified
eplets in HLAMatchmaker is in flux, lack of data on the differential
risk associated with particular eplet mismatches (informed by their
immunogenicity and antigenicity), and a sufficiently diverse donor
pool to facilitate the optimization of HLA compatibility. This review
also highlighted opportunities to overcome some of the challenges
towards the consideration of eplet compatibility, including evolv-
ing rapid high-resolution genotyping techniques, standardization
of antibody-verification efforts, and automation of eplet repertoire
142 | LEMIEUX et al.

and mismatch determination from genotyping data. Large-scale col- epitope database. Human Immunology, 80(2), 103–106. https://doi.
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Elsner, H. A., & Blasczyk, R. (2004). Immunogenetics of
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donor:recipient matching. plantation. Tissue Antigens, 64(6), 687–695. https://doi.
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Engen Rachel M., Jedraszko Aneta M., Conciatori Michael A., Tambur
AC K N OW L E D G E M E N T S
Anat R. (2020). Substituting imputation of HLA antigens for
This work was supported by Genome Canada Large Scale Applied high-resolution HLA typing: Evaluation of a multiethnic popu-
Research Program Award ‘Precision Medicine CanPREVENT AMR' lation and implications for clinical decision making in transplan-
funded by Genome Quebec, Genome British Columbia, Genome tation. American Journal of Transplantation, 1–9. http://dx.doi.
Alberta and Canadian Institutes of Health Research. R.S.-P. is also org/10.1111/ajt.16070
Gu, Y., Wong, Y. H., Liew, C. W., Chan, C. E. Z., Murali, T. M., Yap, J.,
supported by a Fonds de recherche du Quebec—Santé chercheur
Too, C. T., Purushotorman, K., Hamidinia, M., El Sahili, A., Goh, A.
boursier clinician award (grant no. 254386). T. H., Teo, R. Z. C., Wood, K. J., Hanson, B. J., Gascoigne, N. R. J.,
Lescar, J., Vathsala, A., & MacAry, P. A. (2019). Defining the structural
ORCID basis for human alloantibody binding to human leukocyte antigen
allele HLA-A*11:01. Nature Communications, 10(1), 893. https://doi.
William Lemieux https://orcid.org/0000-0001-5684-9773
org/10.1038/s4146​7-019-08790​-1
Ruth Sapir-Pichhadze https://orcid.org/0000-0003-0745-004X Hamada, S., Dumortier, J., Thévenin, C., Pageaux, G.-P., Faure, S.,
Guillaud, O., Boillot, O., Lachaux, A., Luscalov, D.-A., Dubois, V.,
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How to cite this article: Lemieux W, Mohammadhassanzadeh
H, Klement W, Daniel C, Sapir-Pichhadze R. Matchmaker,
matchmaker make me a match: Opportunities and challenges
in optimizing compatibility of HLA eplets in transplantation. Int
J Immunogenet. 2021;48:135–144. https://doi.org/10.1111/
iji.12525