Review article
Critical evaluation of a possible role of HLA epitope matching in kidney transplantation

https://doi.org/10.1016/j.trre.2020.100533Get rights and content

Highlights

  • HLA epitope matching is a new method for the prediction of alloreactivity between donor and recipient HLA alleles.

  • Epitope matching algorithms predict the differences in amino acid sequences, structural and/or physicochemical properties.

  • HLA epitope matching offers a more precise assessment of donor-recipient HLA compatibility and immunological risk.

  • Prevention of de-novo DSA development, acute rejection and graft failure is expected with the application of this method.

  • Avoidance of sensitization by epitope matching can be helpful to decrease the waiting time of re-transplantation patients.

  • Identification of acceptable mismatches at epitope level could play an important role in organ allocation.

Abstract

Human leukocyte antigen (HLA) matching is one of the cornerstones of organ allocation in deceased-donor kidney transplantation. Increased numbers of HLA allele mismatches are associated with a higher risk of immunological rejection, de novo donor-specific HLA antibody development and graft failure. HLA epitopes are defined as the specific portions of HLA molecules to which antibodies and T-cell receptors bind with their paratopes. The same epitope can be present on different HLA alleles. Therefore, HLA matching at the epitope instead of allele level theoretically offers a more precise assessment of donor-recipient HLA compatibility and may more effectively prevent sensitization against foreign tissue. In this review, we describe the different options proposed to define clinically relevant HLA epitopes and critically discuss the potential role of HLA epitope matching in kidney transplantation.

Section snippets

Structural and functional description of HLA epitopes

HLA epitopes are defined as the specific portions of an HLA molecule to which antibodies or T-cell receptors (TCR) bind with their paratopes [1]. An antibody paratope consists of three light-chain and three heavy-chain complementarity determining regions (CDR-L1, −L2, −L3, single bondH1, single bondH2, and single bondH3). A “structural” antigen epitope, consisting of 15–22 amino acids, constitutes the whole binding site for antibodies [13], whereas the 2–5-amino-acid-long functional epitope determines the specificity of

A possible role of HLA epitope matching in kidney transplantation

Table 2 summarizes the studies examining the association between epitope mismatches and clinical outcomes in kidney transplantation. An analysis of United Network for Organ Sharing (UNOS) and Eurotransplant kidney transplant databases between 1987 and 1999 demonstrated that HLA-A and single bondB mismatched kidneys with lower triplet mismatch numbers exhibit almost identical graft survival rates as the zero HLA-A and single bondB antigen mismatched kidneys [28]. Laux et al. found no significant association between

Typical errors

One major critical issue in the evaluation of the superiority of epitope matching over the currently used traditional HLA-A, single bondB, −DR matching is that epitope mismatches by definition correlate with the traditional HLA mismatches and show a collinearity. The consequence is that all clinical outcomes and side effects that are associated with the traditional HLA matching can also be demonstrated with epitope matching. Both HLA as well as epitope matching is based on genetic differences between the

Antigenicity and immunogenicity of HLA epitopes

Unfortunately, the current approaches are insufficient to predict the antigenicity and immunogenicity of HLA epitopes in a specific donor-recipient pair. Our so far obtained results indicate that certain HLA epitope mismatches appear to be more immunogenic than others to drive an alloantibody response [26]. As mentioned earlier, Laux et al. were not able to demonstrate the effect of triplet matching on graft survival on the basis of previously defined immunogenic triplet mismatches.

Future aspects of HLA epitope matching

Considering all fields of application, it is important to wait for further long-term results and to take into account currently existing limitations. Both B- as well as T-cell epitope algorithms might be further improved and combined to deeply understand alloreactivity. Before the current allocation system is shifted to epitope matching, it has to be demonstrated that this method is significantly superior to the conventional HLA matching. Adapting epitope matching to evaluation of zero or only

Conclusions

In conclusion, HLA epitope matching is an attractive candidate to improve assessment of donor-recipient HLA compatibility. A higher epitope load was reported to be associated with dnDSA development, AMR and poor graft survival in recent studies. If its superiority to conventional HLA matching could be proven, epitope-based HLA matching has the potential to play an important role in organ allocation, identification of acceptable mismatches for sensitized patients, estimation of the sensitized

Declaration of Competing Interest

None.

Acknowledgement

We did not receive any specific grant for the content of this review from funding agencies in the public and commercial or non-profit organizations. We started however last year with the company PIRCHE on the same topic a project, which is still ongoing, and received a minor financial grant.

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      Higher HLA epitope mismatch load has related to a higher rate of dnDSA development, higher risk of severe TCMR and AbMR and shorter graft survival [23–25]. Its detection will allow improving organ allocation and individualization of immunosuppression [26]. In our group of kidney transplant recipients, conventional mismatch analysis was not associated with subclinical AbMR, whereas class-II HLA eplet mismatch load related to it.

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    1

    Present address: Ankara University Faculty of Medicine, Department of Nephrology, Ankara, Turkey.

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