In transplantation of hematopoietic stem cells (HSCs) from unrelated donors a high HLA compatibility level decreases the risk of acute graft-versus-host disease and mortality. The diversity of the HLA system at the allelic and haplotypic level and the heterogeneity of HLA typing data of the registered donors render the search process a complex task. This paper summarizes our experience with a search algorithm that includes at the start of the search a probability estimate (high/intermediate/low) to identify a HLA-A, B, C, DRB1, DQB1-compatible donor (a 10/10 match). Based on 2002–2011 searches about 30% of patients have a high, 30% an intermediate, and 40% a low probability search. Search success rate and duration are presented and discussed in light of the experience of other centers. Overall a 9-10/10 matched HSC donor can now be identified for 60–80% of patients of European descent. For high probability searches donors can be selected on the basis of DPB1-matching with an estimated success rate of >40%. For low probability searches there is no consensus on which HLA incompatibilities are more permissive, although HLA-DQB1 mismatches are generally considered as acceptable. Models for the discrimination of more detrimental mismatches based on specific amino acid residues rather than specific HLA alleles are presented. 1. Introduction An increasing number of transplantations are now performed with hematopoietic stem cells (HSC) from unrelated volunteer donors. This trend has been largely facilitated by the impressive growth of volunteer donor registries in the last decade: 8 million donors in 2002 and more than 20 million in 2012. The implementation of recipient and donor HLA high resolution genotyping in the clinical practice has clearly contributed to improve the success of transplantation through a better matching [1, 2]. On the other hand the polymorphism of HLA genes turns out to be much higher than anticipated, resulting in larger difficulties in identifying a perfectly matched donor. Because most donors in the Bone Marrow Donor Worldwide (BMDW) registry are of European descent, searches for patients of other ethnic backgrounds have a lower success rate, particularly for those patients with a mixed origin. HLA matching is commonly based on exons 2 and 3 polymorphism for class I loci and on exon 2 polymorphism for class II loci. The nature of HLA polymorphism with reshuffling of gene segments coding for just a few amino acids has rendered HLA typing a challenging task. The HLA typing techniques currently used in the clinical laboratories often lead
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