Marlies K A Dankers

Leiden University, Leyden, South Holland, Netherlands

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Publications (9)19.76 Total impact

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    ABSTRACT: CD8+ T cell-mediated alloreactivity is generally believed to involve recognition of the alpha1/alpha2 domains of donor-type class I MHC molecules as well as the peptides they bind. Using the CTLp assay outcome as a parameter for the induction of alloreactivity, we have retrospectively surveyed 80 haematopoietic stem cell donor/patient pairs that feature a range of allelic differences at single HLA-A, -B, and -C loci in an attempt to probe the predictive value of such mismatches. In contrast to the expectation that greater degree of allelic disparity would lead to more alloreactivity, we found that in a substantial number of cases, class I MHC molecules with numerous sequence differences did not elicit an allogeneic CTL response. We propose that in generating a T cell repertoire with a sufficiently narrow responsive for self-MHC, positive thymic selection limits the capacity to recognize allogeneic MHC molecules whose structure and sequence have diverged extensively. These findings are important for donor and patient MHC matching strategies and our understanding of T cell-MHC interaction after haematopoietic stem cell transplantation.
    Human Immunology 10/2005; 66(9):969-76. · 2.30 Impact Factor
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    ABSTRACT: Although HLA matching is beneficial in clinical transplantation, it is not feasible to select a completely HLA matched donor for every potential recipient because of the enormous polymorphism of the HLA system. As a consequence, the majority of the recipients will be transplanted with a mismatched donor organ or hematopoietic stem cell transplant. For this large group of patients it is important to take advantage of the differential immunogenicity of HLA mismatches and to select for them a donor with HLA mismatches of low immunogenicity, the so-called acceptable mismatches. The differential immunogenicity of HLA mismatches can be determined by either retrospective analysis of graft survival data or by in vitro assays measuring T-cell and B-cell alloreactivity. A recently developed computer algorithm (HLAMatchmaker) can be instrumental in selecting donors with HLA mismatches, which do not lead to alloantibody formation. The theoretical background and practical implications of this acceptable mismatch approach are discussed.
    Transplant Immunology 09/2005; 14(3-4):187-91. · 1.52 Impact Factor
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    ABSTRACT: Both donor-specific anti-human leukocyte antigen (HLA) antibodies and cytotoxic T lymphocytes are important mediators of graft rejection. HLAMatchmaker determines the amino acid triplets on antibody-accessible sites of the HLA molecule that are not shared between patient and donor. A previous study showed a strong positive correlation between the number of triplet mismatches and the percentage of individuals producing HLA antibodies. In the present study, we tested whether the number of triplet mismatches is predictive for the cytotoxic T-lymphocyte precursor (CTLp) frequency in vitro. The analysis was performed on 108 HLA-DRB1 and DQB1 identical patient-donor combinations registered by the Europdonor foundation, with a single HLA class I mismatch and in healthy responder-stimulator combinations mismatched for at least one HLA class I antigen. The results show that there is no strong correlation between the number of triplet mismatches and the CTLp frequency. Even in the case of zero triplet mismatches, a high CTLp frequency can be found. This lack of correlation is probably caused by the fact that HLAMatchmaker considers only triplets on antibody-accessible positions, whereas CTLs also recognize other epitopes on the HLA molecule, including the bound peptides.
    Transplantation 08/2004; 78(1):165-7. · 3.78 Impact Factor
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    ABSTRACT: The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) and the number of amino acid sequence mismatches was analyzed in patients who rejected a kidney transplant (n=146). A similar analysis was performed for the antibody production of women against the paternal HLA antigens of their child (n=1,397). The amino acid sequence (triplet) differences were analyzed using the HLAMatchmaker algorithm. In both groups, a positive correlation was found between the number of triplet mismatches and the percentage of individuals producing antibodies (P <0.0001). If zero triplet mismatches were present, no antibodies were formed in all cases. When 11 or 12 triplet mismatches were present, 94% of the transplant patients produced antibodies against the donor. In pregnancy, 11 or 12 triplet mismatches led to 27% of the women producing specific antibodies. These results indicate that the immunogenicity of the fetus is lower than that of a rejected kidney and that analysis of the number of triplet mismatches can predict the antibody reactivity against the mismatched HLA antigens.
    Transplantation 05/2004; 77(8):1236-9. · 3.78 Impact Factor
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    ABSTRACT: Recent studies suggest that the immunogenicity of an human leukocyte antigen (HLA) incompatibility should be considered in the context of the HLA phenotype of the recipient. The HLA-DR phenotype of the responder is thought to be predictive for the strength of the alloimmune response. In order to analyze the humoral response against HLA class I antigens in the context of the HLA-DR phenotype of the responder, we selected all HLA-DR homozygous Dutch patients that were present on the Eurotransplant waiting list between 1967 and 2000 (n=1,317 patients). By logistic regression it was determined whether antibody production against a specific HLA class I antigen is associated with a particular HLA-DR antigen in the patient. Furthermore, it was analyzed whether a patient, expressing a particular HLA-DR antigen, preferentially produces antibodies against particular HLA class I antigens. The results demonstrate that patients, homozygous for a certain HLA-DR antigen, cannot be considered high or low responders when analyzing the antibody response in terms of panel reactive antibody (PRA) value. However, a correlation can be found between the HLA-DR phenotype of the patient and the specific antibody response against HLA class I antigens. For example, antibodies against HLA-A10, -A11, -A19, and -B35 are produced more frequently by HLA-DR6 positive individuals, whereas antibodies against HLA-A3, -B5, -B7, -B8, and -B12 are produced more frequently by HLA-DR4 positive individuals. These data confirm that the HLA-DR phenotype of the responder plays a determinative role in the immunogenicity of mismatched HLA antigens. The results indicate that selection of HLA class I mismatches of the donor in the context of the HLA-DR phenotype of the responder might reduce the incidence of humoral graft rejection and minimize the sensitization grade of retransplant candidates.
    Human Immunology 02/2004; 65(1):13-9. · 2.30 Impact Factor
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    ABSTRACT: The increased graft survival obtained with poorly matched kidney grafts is for many clinicians a reason to reconsider the value of HLA matching in today’s renal transplantation. Although many other parameters are important, there are still arguments to continue selection of donors on the basis of HLA compatibility with the recipient. Even with the current, very efficient immunosuppression, fully HLA matched combinations have a significantly better graft survival. Furthermore, antibody formation during graft rejection is directly related to the number of mismatched HLA epitopes on the donor organ. HLA matching will prevent that retransplant candidates become highly sensitized, and the incidence of skin cancer after transplantation is significantly lower in HLA matched combinations. Finally, it is to be expected that the threshold to taper or stop the immunosuppression will be lower in HLA matched combinations. As long as the induction of clinical transplantation tolerance is not a routine procedure, a significant proportion of the patients will benefit from a fully HLA matched kidney donor.
    Transplantation Reviews. 01/2004;
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    ABSTRACT: More insight into the differential immunogenicity of human leukocyte antigen (HLA) mismatches will be beneficial for donor selection in clinical transplantation. In this study the immunogenicity of HLA antigens was analyzed by examining the antibody profiles in women who have been pregnant. In total 888 women, who had pregnancy induced HLA alloantibodies, were included in this study, while 413 women who had not been immunized by their pregnancy, served as controls. First it was analyzed whether women expressing particular HLA antigens are more likely to produce HLA alloantibodies. Next we determined whether certain HLA mismatches of their children are more immunogenic than other ones. Finally we studied whether the immunogenicity of specific HLA mismatches is dependent on the HLA phenotype of the women. Women expressing HLA-A3, HLA-A32, and HLA-B21 are more likely to produce alloantibodies whereas women expressing HLA-B13 and HLA-B17 have a significantly lower incidence of alloantibodies compared with women expressing other HLA antigens. Children with HLA-A2 or HLA-B5 mismatches induced alloantibodies significantly more often whereas children with HLA-A30, -A31 or -A33 and HLA-A28 induced alloantibodies significantly less often than children with other HLA class I mismatches. Finally we could demonstrate that the immunogenicity of a particular HLA mismatch is dependent on the HLA phenotype of the women. Information on the differential immunogenicity of HLA mismatches may be of benefit for the determination of acceptable and taboo mismatches in the case of donor selection for (highly sensitized) patients.
    Human Immunology 07/2003; 64(6):600-6. · 2.30 Impact Factor
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    ABSTRACT: The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules.
    Transplantation 02/2003; 75(3):418-20. · 3.78 Impact Factor
  • Human Immunology - HUM IMMUNOL. 01/2003; 64(10).

Publication Stats

133 Citations
110 Downloads
530 Views
19.76 Total Impact Points

Institutions

  • 2004
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2003–2004
    • Leiden University Medical Centre
      • Department of Immunhematology and Blood Transfusion
      Leiden, South Holland, Netherlands