Unrelated cord blood transplantation (UCBT) is increasingly performed as an alternative treatment for patients who need hematopoietic cell transplantation (HCT) but lack an immediate access to an HLA compatible bone marrow or peripheral blood donor, thus currently comprising approximately 30% of the total allogeneic HCT in our country. Although the clinical significance of HLA matching in UCBT has been so far controversial, the increasing size of UCBT datasets now allows us more reliable analysis on the impact of HLA compatibility on the clinical outcomes of UCBT. In this short review, we summarize the results of most recent studies addressing the role of HLA matching in UCBT and propose an algorithm for selecting an appropriate cord blood unit for HCT.

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Alloreactivity of T cells is a main cause of rejection of allografts, and it depends on direct T-cell recognition of and reaction to the allogenic HLA (allo-HLA) molecules. If the mechanisms underlying this great paradox in immunology, in which T cells must stringently discriminate ‘non-self peptide’ from ‘self peptide’ in a self-HLA-restricted manner, while a large number of T cells show allo-HLA reactivity, were solved, it would be tremendously beneficial for patients receiving transplantation medicine. Accumulating knowledge for the crystal structures of TCR/peptide/allo-HLA (MHC) complexes has enabled us to compare them to the structures of TCR/cognate ligand, that is, TCR/non-self peptide/self-HLA (MHC) complexes. It has been shown that there are at least three patterns of T-cell allo-recognition; 1) molecular mimicry, 2) induced fit and 3) disparate docking. Since not only TCRs but also peptides and HLAs (MHCs) are so flexible to form the three-member complexes, there is no uniform mechanism of T-cell allo-recognition so far and it is yet difficult to predict the magnitude of T cell reactivity to the certain combination of allo-HLAs before transplantation. So, the basic mechanisms underlying the T-cell allo-recognition are awaited to be determined by accumulation of more crystal structures of the same TCRs interacting with their cognate ligands and with allo-ligands (peptide/allo-HLAs (MHCs)). Finally, it was recently reported that, in murine experiments, the production of antidonor-HLA-specific IgG antibodies in the recipients after transplantation is exclusively mediated by the recipient helper T (Th) cells indirectly recognized allogenic donor MHC-derived peptides presented by the MHC class II molecules expressed on the surface of recipient B cells. The importance of Th cells activated by indirect allorecognition for the differentiation of B cells into plasma cells producing long-lasting anti-donor-HLA-specific IgG antibody that mediates chronic allograft rejection has been elucidated.

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Various methods have been proposed for the testing of HLA antibodies in organ transplantation. These methods include cross-matching using donor lymphocytes, and panel reactive antibody (PRA) tests using synthetic beads coated with purified HLA molecules or extracted HLA antigens. However, currently, depending on the testing method, the results can be difficult to determine due to differences in detection sensitivity, differences in the classes/subclasses of immunoglobulin composing the donor-specific alloantibodies (DSA), and instances where non-HLA antibodies such as natural antibodies or autoantibodies react. In this lecture, I will introduce the testing and analysis methods that are routinely used for HLA antibody testing at our institution.

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