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Front Immunol. 2014 Oct 27;5:547. doi: 10.3389/fimmu.2014.00547. eCollection 2014.

Association between CTL Precursor Frequency to HLA-C Mismatches and HLA-C Antigen Cell Surface Expression.

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Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands ; Tissue Typing Laboratory, Rabin Medical Center , Petach Tikva , Israel.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands.
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc. , Frederick, MD , USA ; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University , Boston, MA , USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, WA , USA.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center , Leiden , Netherlands ; Europdonor Foundation , Leiden , Netherlands.


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.


CTLp assay; HLA-C; allo-reactivity; cell surface expression; cytotoxic T-cell precursor frequency

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