Maximizing the Benefits of Hla Matching for Renal Transplantation: Alleles, Specificities, Cregs, Epitopes, or Residues?

Evaluation of HLA Matching for CREG Antigens in Europe. Transplantation 1999; 68: 1097. Wujciak T, Opelz G. Although controversial, organ allocation on the basis of HLA matching has been widely adopted in renal transplants. Since the discovery of HLA as the dominant histocompatibility system in humans and identification of its role as the principle mediator of transplant rejection, strategies have evolved to reduce the capacity of the immune system to destroy healthy organ grafts. Therapeutic approaches to attenuate transplant rejection through diminution of the immune response by minimizing donor and recipient HLA incompatibilities has contributed toward improved transplant outcome (1). The debate about the benefits of HLA matching for cadaveric donor renal transplants has ensued since the first human MHC antigens were identified in the 1960s. Since this time, the initial use of rudimentary HLA typing reagents capable of defining only a limited number of polymorphisms has now given way to sophisticated DNA sequence based techniques. Advances in both serological and DNA-based HLA typing have enhanced our understanding of the nature of the HLA products and facilitated their resolution at both the tertiary protein and amino-acid sequence levels. The products of HLA can now be resolved at several levels, depending on the methodology used (Table 1).Table 1: Approaches to maximize the number of "beneficially" HLA matched transplantsaConventional HLA matching policies use alloantisera- and monoclonal antibody-defined "private" epitopes carried on individual HLA specificities. This defines the "broad" and/or "split" antigens that are widely used for organ allocation. DNA-based technology can further resolve sequence variants of these specificities and is capable of distinguishing single amino acid polymorphisms at the "allele" level, the majority of which are indistinguishable using serologic methods. However, although strongly implicated for negating graft versus host disease after bone marrow transplants, a role for "high resolution" allele matching in renal transplants has yet to be firmly established. Furthermore, the ever increasing number of HLA variants has prompted several investigators to consider the logistics of matching for such a diverse polymorphic antigenic system. In common with other polymorphic systems, close examination of DNA sequences at individual HLA loci reveals that, for each DNA base, the majority of nucleotide substitutions are no more than dimorphic. There is, therefore, only limited polymorphism at any given amino acid position and common sequence motifes are often shared by closely related HLA alleles and specificities. This interrelationship gives rise to serological cross-reactive groups (CREGs) and the concept of amino acid residue and epitope matching. Such cross-reactive groups are recognized with allo- or monoclonal-antibodies specific for antigenic single amino acid polymorphisms and/or sequence motifes. Therefore, the large number of HLA alleles can be reduced to a small number of common antigenic epitopes shared by HLA specificities (i.e. "public" antigens or CREGs) (2). Furthermore, because many CREGs have been characterized using sera collected from sensitized patients after transplant rejection, there is evidence that such epitopes constitute clinically relevant immunogenic targets expressed on donor tissue. Retrospective studies, performed mainly in North America, have examined the impact of various antibody-defined amino acid residue and "public" epitope matching algorithms on kidney transplant outcome. An adverse effect on graft survival was shown to be associated with increasing mismatches for serologically-defined determinants and amino acid residues. Data from both the United Network for Organ Sharing and the South-Eastern Organ Procurement Foundation as well as smaller single center studies indicate that, with separate consideration of zero HLA-A, -B, and -DR mismatches, matching for common CREGs is effective for enhanced prognosis (3-5). Furthermore, by reducing the HLA-A and -B specificities to just 10 CREGs, the limited polymorphism facilitates the opportunity to HLA match on a local basis, without the need for donor organ exchange (4). In addition, projections of potential organ allocation on the basis of CREG matching particularly favours non-white ethnic groups who are otherwise disadvantaged when using specificity matching alone (5). This edition of Transplantation features an article from Wujciak and Opelz that challenges the validity of these findings. Their contention is that, because many organs are allocated on the basis of minimizing donor and recipient HLA specificity mismatches, there is a disproportionately high level of matched transplants within the CREG-matched cohorts. Such a bias may lead to an observed effect of "public" antigen matching that is actually a result of the underlying high number of "private" antigen-matched cases. They have considered the effect of CREG matching on transplants performed in Europe, and stratified their analysis by conventional "split" specificity matching. These data show that there is no independent benefit of CREG-matched transplants in the absence of specificity matching. Furthermore, transplant waiting list simulations demonstrate that the application of the algorithm incorporating CREG matching that is currently being piloted by transplant centers in the USA would not give rise to the predicted benefit in terms of prolonged transplant half-life. The question, therefore, arises as to whether the difference between the data from the USA and European data is method of analysis or differing policies and their effects on transplant outcome. A comparison of transplants performed in Germany and the USA shows that 79% of transplants performed in the USA were mismatched for three or more HLA specificities, compared with only 44% in Germany (1). Both the German and USA data showed a strong influence of HLA matching on transplant outcome, which, because of the higher number of matched cases in Germany, translated into a significantly higher success rate. These data also indicate that there is a much smaller bias of concomitant specificity matching in the CREG matched groups in the USA than in Europe. Therefore, the American data are less likely to be influenced by the underlying effects of specificity matching. Clearly, the onus now rests with the United Network for Organ Sharing and the South-Eastern Organ Procurement Foundation registries to perform similar analyses to formally exclude this possibility. Furthermore, the strong influence of HLA-DR compatibility has not been considered and warrants inclusion in the simulations on CREG matching and transplant outcome. Finally, matching for CREGs has been shown to benefit highly sensitized patients, because crossreactive antigens frequently constitute acceptable mismatches with an increased chance of obtaining a negative donor lymphocyte crossmatch. Such findings are of fundamental importance to the field of organ allocation and are likely to influence future policies. Past experience has shown that, in general, the more discerning the matching criteria-the greater the correlation with graft outcome. Therefore, although the benefits of HLA matching for improved transplant survival rates are now widely accepted, the debate concerning the level at which an HLA match becomes "beneficial" and what is actually achievable, continues. Craig J. Taylor Tissue Typing Laboratory; Addenbrooke's Hospital; Cambridge CB2 2QQ Philip A.