Abstract
Previous studies showed the relevance of the cytotoxic T-cell precursor (CTLp) frequency assay for prediction of the outcome of HLA mismatched hematopoietic cell transplantation (HCT). Recently, it has been shown that HLA-C cell surface expression is correlated with virus specific cytotoxic T-cell responses and viremia control in HIV patients. The aim of the current study was to investigate the association between HLA-C antigen expression and the CTLp frequency to the mismatched HLA-C antigen. In total 115 recipient–donor pairs, for whom a successful CTLp assay was performed, were evaluated for this pilot study. All donor–recipient pairs were matched at 9/10 alleles with a single mismatch at the HLA-C locus. Antigen expression level of the mismatched HLA-C allele for each recipient and donor was based on the mean fluorescence intensity (MFI) values as described by Apps et al. (1). The cell surface expression of recipient’s mismatched HLA-C antigen was significantly lower among CTLp negative (n = 59) compared to CTLp positive (n = 56) pairs (154 and 193 MFI units, respectively, p = 0.0031). This difference was more pronounced in donor–recipient pairs that were mismatched for amino-acid residue-116 located in the groove of the HLA-C antigen, suggesting that the importance of peptide binding in the allo-recognition. Furthermore, in the particular case of low expression of the recipient mismatched HLA-C antigen (MFI < 115), CTLp reactivity depended on HLA-C expression level in the donor, the median MFI of donor’s mismatched HLA-C antigen was 114 in CTLp negative cases (n = 26), while in CTLp positive cases (n = 15) the median MFI of donor’s HLA-C antigen was 193 (p = 0.0093). We conclude that the expression level of the donor and recipient mismatched HLA-C antigens affect CTLp outcome. HLA-C antigen expression levels in combination with the CTLp assay may prove useful for the prediction of the clinical outcome of HLA-C mismatched HCT.
Highlights
Matching of HLA-C alleles between donor and recipient is associated with favorable outcome in hematopoietic cell transplantation (HCT) [2] and in cord blood transplantation [3]
killer-immunoglobulin receptors (KIR)-ligand compatibility prediction was based on donor and recipient HLA-B and HLA-C allelic resolution typing using the KIR-ligand calculator provided in the Immuno Polymorphism Database website of the European Bioinformatics Institute [13]
As described by Ruggeri et al [14], KIR-ligand compatibility was defined as presence in recipients of donor Class I allele antigen groups recognized by KIRs, and incompatibility was defined as absence in the recipient of donor Class I antigen groups recognized by KIRs
Summary
Matching of HLA-C alleles between donor and recipient is associated with favorable outcome in hematopoietic cell transplantation (HCT) [2] and in cord blood transplantation [3]. Previous studies showed the relevance of the cytotoxic T-cell precursor (CTLp) frequency assay for predicting outcome of HLA mismatched HCT [6]. Patient survival is significantly better if no cytotoxic T-cells (CTLs) are present in the donor versus the recipient’s HLA mismatched antigen, compared to a donor–recipient combination with a positive CTLp test [7]. Several approaches for characterizing differential allo-reactivity amongst HLA mismatches have been suggested, such as compatibility in killer-immunoglobulin receptors (KIR) or at specific amino-acid residues.
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