Can Acceptable Hla Mismatches Be Predicted

Even with the large number of prospective donors listed by the various registries around the world, many patients do not find a matched donor even for HLA-A, -B, -C, -DRB1*. Despite the increased risk associated with HLA-mismatched transplants, acceptable results are achieved for many patients despite an imperfectly matched donor. The question raised is whether certain HLA mismatches are better tolerated than others and if so, whether this can be applied to donor selection to improve outcome.

Comparing different prospective allele mismatches simply on the basis of the number of mismatched amino acids is unlikely to be helpful. More likely to be useful would be a qualitative analysis of the mismatched residues. As discussed previously, most allore-active T cells recognize foreign MHC in a peptide-dependent or a peptide-specific fashion,33-38 leading to the speculation that HLA amino acids involved in pep-tide binding and TCR interaction may be more important to matching than other positions (see Figure 93.5). Antigen-level class I mismatches pose a greater risk than allele-level mismatches for graft failure112 and increased mortality.106 Petersdorf and colleagues23 observed that there were a greater number of differences in peptide binding and especially TCR contact residues in the antigen-mismatched donor/recipient pairs rather than in allele-level mismatched donor/ recipient pairs. Ferrara and colleagues131 found that transplanted patients whose donors were mismatched at residue 116 of HLA class I molecules (A, B, or Cw) were at higher risk of severe GVHD and increased mortality than those with mismatches at other residues.131 This residue is in the floor of the cleft and is expected to contribute to peptide-binding specificity.19 In addition to the molecular position of the mismatched residue, the nature of the mismatched amino acid may relate to the impact of the change. Substitution with amino acids of similar character may have less effect than that with dissimilar amino acids.

The ability to associate particular HLA allele mismatches with different levels of complication risk would be useful to distinguish among mismatched prospective donors. Elsner and colleagues24,132 have developed an online tool that compares HLA alleles based on quantitative, positional, and qualitative evaluation of the mismatched amino acids and produces a dissimilarity score ( Shaw and colleagues133 studied 26 HLA-A allele level mismatched transplants but did not find a correlation of the dissimilarity scores and transplant outcome. That HLA allele pairs can be compared with regard to probability of T-cell stimulation is a logical premise. However, further large studies of HLA allele level typed transplant pairs will be needed to determine clinical validity of this approach.

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