Antirecipient helper and cytotoxic T-cell frequencies in bone marrow transplantation

Kwok, Janette; Leung, Anskar Y.H.; Lee, T L; Lau, Yu Lung; Chu, Patrick; Jones, B.; Hawkins, B. R.; Liang, Raymond

doi:10.1038/sj.bmt.1704566

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…Quantification of the allogeneic CTL response in vitro was obtained by the CTLp assay (6), because it has been proven to be clinically relevant in predicting allogeneic HSCT outcome (7)(8)(9)(10)(11)(12)(13). These studies focused on the amino acid differences on those parts of MHC class I molecules that are important for TCR contact and/or peptide binding.…”

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confidence: 99%

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

Jöris

Rood

Roelen

et al. 2012

The Journal of Immunology

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Previously, we showed that with an increasing number of amino acid differences in single HLA class I-mismatched molecules, the probability of T cell alloreactivity decreases. It is unlikely that every amino acid difference will affect T cell alloreactivity in a similar way; we hypothesized that the effect of an amino acid difference may be dependent on its position and/or physicochemical properties. We selected 131 patient/donor pairs with either a single HLA-A or -C mismatch in the graft-versus-host direction and that were compatible for HLA-B, -DRB1, and -DQB1. The alloreactive CTL precursor (CTLp) frequency was determined and associated with the amino acid differences between the single HLA class I mismatches. In the β sheet, only amino acids that are noncompatible in their physicochemical properties affect T cell alloreactivity, whereas in the α helices, both compatible and noncompatible amino acids affect CTLp outcome. Positions 62, 63, 73, 76, 77, 80, 99, 116, 138, 144, 147, and 163 were bivariately associated with CTLp outcome, irrespective of the total number of amino acid differences. In multivariate analysis, positions 62, 63, 73, 80, 116, 138, 144, and 163 were found to be most predictive for negative CTLp outcome. These results formed the basis for a weighted predictive mismatch score; pairs with the highest mismatch scores are estimated to be 13 times more likely to have a negative CTLp. This new algorithm may be a tool in donor selection for hematopoietic stem cell transplantation.

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confidence: 99%

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

Jöris

Rood

Roelen

et al. 2012

The Journal of Immunology

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“…Multiple publications have reported that the CTLp frequency assay is able to predict clinical outcome of HCT ( 7 , 19 – 21 ), which is the reason why this assay is incorporated in the clinical decision making of donor selection in several Dutch transplant centers ( 6 ). The CTLp assay quantifies the frequency of donor CTLp’s capable of responding to mismatched HLA Class I antigens presented on the recipient’s cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…, 1997; Van der Meer et al. , 2000; Kwok et al. , 2004) and are also indicative of HLA antigenic variants (Barnardo et al.…”

Section: Introductionmentioning

confidence: 99%

“…High host-specific pretransplant cytotoxic T-lymphocyte precursor (CTLp) frequencies can be detected in patients developing acute GvHD after unrelated HLA-matched bone marrow transplantation (Kaminski et al, 1989;Schwarer et al, 1994;Spencer et al, 1995;Keever-Taylor et al, 1997;Van der Meer et al, 2000;Kwok et al, 2004) and are also indicative of HLA antigenic variants (Barnardo et al, 1996;Speiser et al, 1996;Scott et al, 1998;Van der Meer et al, 2000). Also, high host-reactive donor helper T-lymphocyte precursor (HTLp) frequencies have been shown to be associated with the incidence and severity of acute GvHD and to detect mismatches in HLA class II (Schwarer et al, 1994;Potolicchio et al, 1996;Keever-Taylor et al, 1997;Russel et al, 2001;Kwok et al, 2004) and even HLA class I antigens (Schwarer et al, 1994;Keever-Taylor et al, 1997). However, other studies suggest that determination of host-reactive donor CTLp and HTLp frequencies is not predictive for the development of acute GvHD (Fussel et al, 1994;Montagna et al, 1996;Pei et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

T‐cell precursor frequencies and long‐term outcome following unrelated hematopoietic stem cell transplantation

Kircher

Niederwieser

Gächter

et al. 2008

Int J Lab Hematology

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Functional assays measuring alloreactivity of donor cells are desired to detect either cryptic epitopes inducing graft-vs.-host disease (GvHD) after human leukocyte antigen (HLA)-identical hematopoietic stem cell transplantation (HSCT) or permissible HLA mismatches. However, their value in predicting GvHD and survival is still limited. We determined the cytotoxic and helper T-cell precursor (CTLp and HTLp) frequencies by limiting dilution analysis (LDA) in 40 unrelated recipient/donor combinations. The median observation period at the time of this writing was 4.44 years (range from 0.1 to 11.28). Better overall survival was observed in patients with rather low host-specific CTLp and HTLp frequencies, whereas a trend toward high CTLp frequencies was seen in patients with higher incidence of acute GvHD, especially in patients mismatched in HLA-C. CTLp and HTLp frequencies did not correlate with the incidence of chronic GvHD and relapse. In conclusion, we detected a trend toward better overall survival of patient/donor pairs with low CTLp and HTLp frequencies, however, recommend to use LDA as an additional tool for identifying the most suitable donor when more than one fully HLA-matched stem cell donor is available.

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Antirecipient helper and cytotoxic T-cell frequencies in bone marrow transplantation

Cited by 5 publications

References 26 publications

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

A Proposed Algorithm Predictive for Cytotoxic T Cell Alloreactivity

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

T‐cell precursor frequencies and long‐term outcome following unrelated hematopoietic stem cell transplantation

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