In recent years, umbilical cord blood (CB), a rich source of hematopoietic stem cells (HSC), has been used successfully as an alternative HSC source to treat a variety of hematologic, immunologic, genetic, and oncologic disorders. CB has several advantages, including prompt availability of the transplant, decrease of graft versus host disease (GVHD) and better long-term immune recovery, resulting in a similar long-term survival. Studies have shown that some degree of HLA mismatches is acceptable. This review is intended to outline the main aspects of HLA matching in different settings (related, pediatric, adult, or double-unit HSCT), its effect on transplantation outcome and the role of HLA in donor selection. 1. Introduction The experience of the last 20 years indicates that cord blood transplantation is a valid alternative to bone marrow (BM) and PBSC transplants. For patients suffering from malignant or nonmalignant diseases, who do not have a matched sibling donor or a matched volunteer unrelated donor, two available alternative stem cell donor sources exist: a haploidentical transplantation from a three locus mismatched family member (parents, siblings) or an unrelated cryopreserved umbilical cord blood (CB) unit from a cord blood bank [1–4]. A low rate of graft versus host disease (GVHD) in the presence of higher HLA disparity, represents the main advantage of the umbilical cord grafts, while delayed engraftment due to limited cell dose is still the major drawback [3]. Moreover, umbilical cord blood is a viable source particularly for racial and ethnic minority patients whose genetic variations are not included in unrelated volunteer donor registries [5]. The role of HLA mismatches in CBT remains unclear as most transplants have been selected on low resolution class I HLA typing and allelic level class II typing. In malignant diseases, HLA mismatching is partially overcome by increasing the cell dose [6]. Recent data on associations between HLA disparity and survival, support that there is a direct association between the number of donor-recipient HLA mismatches and the risk for GVHD, while the mismatching has a greater impact on absolute mortality differences in recipients with diseases with low risk of posttransplant recurrence [7]. The number of CB transplantations, as well as the global inventory of CB units, are growing rapidly. CB grafts, in contrast to adults unrelated donors who need 10/10 allele level matches with the patients, have a reduced risk of severe GVHD and permit a mismatched transplantation at least in one HLA locus [8, 9]. HLA
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