The long and winding road towards epitope matching in clinical transplantation

Abstract

Recent data suggest that HLA epitope matching is beneficial for the prevention of de novo donor specific antibody (DSA) formation after transplantation. In this review, different approaches to predict the immunogenicity of an HLA mismatch will be discussed. The parameters used in these models are often called epitopes but the actual antibody epitope is far more complex. Exact knowledge of the antibody epitope is crucial if epitope matching is also used as a tool to select compatible donors for (highly) sensitized patients. Evidence is provided that it is not always possible to give an exact definition of an antibody epitope. We conclude that HLA "epitope" matching is superior over HLA antigen matching with respect to the prevention of de novo DSA formation and will enhance the prediction of acceptable HLA mismatches for sensitized patients. However, epitope matching at our current level of knowledge will not solve all histocompatibility problems as unexpected antibody reactivity still may occur.

Keywords: HLA matching; antibodies; epitopes; immunogenicity; virtual crossmatch.

Figure 1

HLA alleles can be considered as a string of potential antibody epitopes. A specific HLA allele consists of a unique set of epitopes while the individual epitopes can be shared with other alleles. The consequence is that the number of foreign epitopes on an individual HLA mismatch can differ and depends on the HLA type of the potential antibody producer. It is to be expected that the HLA mismatch of donor A (four foreign epitopes for the patient) is more immunogenic than the one of donor C (only one nonself epitope).

Figure 2

The production of IgG antibodies depends on a specific interaction between CD4 + T cells and B cells. 1: The B cell receptor recognizes an epitope on a foreign HLA molecule. 2: This leads to internalization of the target antigen, which is then degraded into peptides. 3: Some of these peptides bind to the HLA class II molecules on the B cell and the foreign (nonself) peptides are recognized by CD4 + T cells. 4: his leads to activation of the T cells associated with the production of immunoregulatory molecules. 5: These molecules trigger a class switch of the antibodies produced.

Figure 3

Foot prints of three human monoclonal antibodies on their target antigens. (a) The reactivity of monoclonal MUS4H4 depends only on sharing of the immunogenic epitope with the HLA molecule, which has triggered the production of this antibody. (b) For the reactivity of monoclonal antibody VTM9A10 sharing of both the immunogenic epitope and an additional contact site with the immunizing antigen is crucial. (c) The reactivity of monoclonal antibody WIM8E5 is very complex. It appears that the reactivity with HLA‐A antigens depends on sharing of the immunogenic epitope and an additional contact site. The observed cross‐reactivity with HLA‐B and –C antigens has completely different requirements. The reactive HLA‐C alleles have one particular polymorphic position in common (in green) whereas the basis of the reactivity with HLA‐B targets remains unclear. Note: more details on the immunizing effect leading to the production of these antibodies is given in table 2.