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Publications (1,015)
Recurrent pregnancy loss (RPL) affects 1-2% of couples who are trying to conceive. At some point, some couples do maintain a healthy pregnancy to term, but the underlying mechanism of RPL remains elusive. Human leukocyte antigen (HLA)-G is an immune modulatory molecule. Our group previously showed increased HLA-G levels in the decidua of term pregn...
In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to ot...
With the emergence of immunotherapies, the understanding of functional HLA class I antigen presentation to T cells is more relevant than ever. Current knowledge on antigen presentation is based on decades of research in a wide variety of cell types with varying antigen presentation machinery (APM) expression patterns, proteomes and HLA haplotypes....
In oocyte donation (OD) pregnancy, a fetus can be completely allogeneic to the recipient. Consequently, the maternal immune system has to cope with greater immunogenetic dissimilarity compared to naturally conceived pregnancy. Previously, we showed an association between successful OD pregnancy and lower immunogenetic dissimilarity, reflected by th...
Dendritic cells (DCs) are key in shaping immune responses and are recruited to the human cervix after coitus by seminal plasma (SP). SP has been shown to skew the differentiation of monocyte-derived DCs towards an anti-inflammatory profile when cultured in medium containing fetal calf serum (FCS). Here, we confirmed that SP skewed DCs cultured in f...
In the field of transplantation, the humoral immune response against mismatched HLA antigens of the donor is associated with inferior graft survival, but not in every patient. Donor‐specific HLA antibodies (DSA) of different IgG subclasses may have differential effects on the transplanted organ. Recombinant technology allows for the generation of I...
Soluble HLA‐G (sHLA‐G) levels in human seminal plasma (SP) can be diverse and may affect the establishment of maternal‐fetal tolerance and thereby the outcome of pregnancy. We investigated whether sHLA‐G levels in SP are associated with polymorphisms in the 3'‐untranslated region (UTR) and UTR haplotypes of the HLA‐G gene. Furthermore, we compared...
Kidney transplantation is the best treatment option for patients with end‐stage renal disease (ESRD). The waiting time for a deceased donor kidney in the Netherlands is approximately 3 years. Mortality among patients on the waiting list is high. The aim of the PROCARE consortium (PROfiling Consortium on Antibody Repertoire and Effector functions) w...
The Eurotransplant acceptable mismatch program has been shown to be a successful tool to enhance transplantation of highly sensitized patients. However, patients with rare HLA phenotypes in relation to the Eurotransplant donor population remain on the waiting list. EUROSTAM is an EU funded project to explore the feasibility of a Europe‐wide accepta...
Background:
HLA-specific memory B cells may contribute to the serum HLA antibody pool upon antigen re-exposure. The aim of this pilot study was to investigate the presence of concurrent donor-specific memory B cell-derived HLA antibodies (DSA-M) in renal allograft recipients with pretransplant donor-specific HLA antibodies (DSA) and its associatio...
Introduction
Oocyte donation (OD) enables women with reproductive failure to conceive. Compared with naturally conceived (NC) and in vitrofertilisation (IVF) pregnancies, OD pregnancies are associated with a higher risk of pregnancy complications. The allogeneic nature of the fetus in OD pregnancies possibly plays a role in the development of these...
The clinical significance of non‐HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large‐scale studies incorporating analysis of multiple non‐HLA antibodies simultaneously. We developed a multiplex non‐HLA antibody assay against 14 proteins highly expressed in the kidney. In this st...
Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, determined by extensive laboratory test...
Fig. S1. (a) Quantification of CD20+ B cell infiltrates in biopsies from grafts undergoing AR and during stable graft function in an independent validation cohort. (b) Gene expression levels for MS4A1 are elevated in biopsies from grafts undergoing AR compared to biopsies during stable graft function in an independent validation cohort.
Fig. S2. A...
Abacavir administration is associated with drug induced hypersensitivity reactions in HIV+ individuals expressing the HLA‐B*57:01 allele. However the immunological effects of abacavir administration in an HLA‐B57 mismatched transplantation setting has not been studied. We hypothesized that abacavir exposure could induce de‐novo HLA‐B57 specific all...
Tissue-resident memory T (TRM) cells are characterized by their surface expression of CD69 and can be subdivided in CD103+ and CD103− TRM cells. The origin and functional characteristics of TRM cells in the renal allograft are largely unknown. To determine these features we studied TRM cells in transplant nephrectomies. TRM cells with a CD103+ and...
Donor and third-party reactive IL-21 producing cells.
A typical example of the phenotypic analysis of CD4+ and CD8+ naïve (CD45RA+CCR7+), central memory (CD45RA−CCR7+), effector memory (CD45RA−CCR7−), and EMRA (CD45RA+CCR7−) T cells in thawed PBMC.
Intra- and inter-assay variability.
Interleukin (IL)-21 supports induction and expansion of CD8⁺ T cells, and can also regulate the differentiation of B cells into antibody-producing plasma cells. We questioned whether the number of circulating donor-specific IL-21 producing cells (pc) can predict kidney transplant rejection, and evaluated this in two different patient cohorts. The f...
Successful pregnancy outcome depends on local immunoregulatory mechanisms preventing a detrimental immune response towards the semi-allogeneic fetus. We investigated the influence of HLA-DR (in)compatibility on pregnancy outcome parameters in 480 women. The parameters tested were birth weight, individualized birthweight ratio (IBR), gestational age...
During pregnancy, maternal T cells can enter the foetus, leading to maternal-foetal chimerism. This phenomenon may affect how leukaemia patients respond to transplantation therapy using stem cells from cord blood (CB). It has been proposed that maternal T cells, primed to inherited paternal HLAs, are present in CB transplants and help to suppress l...
A possible way of immunomodulation of the maternal immune system before pregnancy would be exposure to paternal antigens via seminal fluid to oral mucosa. We hypothesized that women with recurrent miscarriage have had less oral sex compared to women with uneventful pregnancy.
In a matched case control study, 97 women with at least three unexplained...
B cells have various functions besides being plasma cell precursors. We determined the presence of intragraft B cells at time of acute rejection (AR) and looked for correlates of B cell involvement in peripheral blood.
Renal biopsies at time of AR or stable graft function were analyzed for the presence of B cells and B cell‐related gene expression,...
A single observation in a patient with an unusual transfusion reaction led to a life-long fascination with immunogenetics, and a strong wish to improve the care for patients needing a transplantation. In 2017, Jon van Rood, one of the pioneers in the field of HLA and immunogenetics of transplantation, passed away. Several obituaries have appeared d...
Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3′UTR) of the HLA-G gene can affect the level of HLA-G expression, which may be altered in women with recurrent miscarriages (...
Recent data suggest that HLA epitope matching is more predictive for the formation of donor specific antibodies (DSA) after transplantation than classical HLA antigen matching.
A proper definition of the epitopes and their immunogenicity is crucial for a broad clinical application of epitope matching in solid organ transplantation.
For that purpose...
Kidney transplantation is considered the favored treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagn...
Heterologous immunity of virus-specific T cells poses a potential barrier to transplantation tolerance. Cross-reactivity to HLA-A and -B molecules has broadly been described, whereas responses to allo-HLA-C have remained ill defined. In contrast to the transplant setting, HLA-C is the only polymorphic HLA molecule expressed by extravillous trophobl...
The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies direct...
Background:
Pretransplant immunological risk assessment is currently based on donor-specific HLA antibodies in serum. Despite being an excellent source for antibodies produced by bone marrow-residing plasma cells, serum analysis does not provide information on the memory B-cell compartment. Although B-cell culture supernatants can be used to detec...
Background:
Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nD...
Introduction
Oocyte donation pregnancies are associated with a higher incidence of pregnancy complications, such as pre-eclampsia. In OD pregnancies the fetus may be completely allogeneic to the mother, since the fetus carries paternal and donor derived Human Leukocyte Antigen (HLA) genes. The higher incidence of pregnancy complications might be re...
Recent data suggest that HLA epitope matching is beneficial for the prevention of de novo donor specific antibody (DSA) formation after transplantation. In this review, different approaches to predict the immunogenicity of an HLA mismatch will be discussed. The parameters used in these models are often called epitopes but the actual antibody epitop...
Virus-specific T cells have been shown to cross-react with allogeneic HLA (allo-HLA) at a clonal level. However, the impact of a single virus on the allorepertoire has never been investigated at the polyclonal level.
We made an inventory of the incidence and specificity of allo-HLA-cross-reactive-virus-specific CD8⁺ T cells in 24 healthy individual...
High titers of HLA antibodies are associated with platelet refractoriness, causing poor platelet increments after transfusions in a subset of patients with HLA antibodies. Currently, we do not know the biological mechanisms that explain the variability in clinical responses in HLA alloimmunized patients receiving platelet transfusions. Previously w...
The observation, by Ray Owen and colleagues in 1954, that D-negative women were less likely to form anti-D antibodies against their D-positive fetus if their mother possessed the D-antigen, was not found in all later studies. We hypothesized that breastfeeding, received by the mother, may affect her immunity against non-inherited maternal red blood...
Luminex single antigen bead assays revolutionized HLA antibody detection owing to their superior sensitivity compared to conventional methods. Nevertheless, the advent of higher sensitivity came at the expense of difficulty in clinical decision‐making, since not all luminex detectable antibodies are clinically relevant. Therefore, new tools such as...
Background:
There is no consensus in the literature on the interpretation of single antigen bead (SAB) positive for a specific HLA antibody.
Methods:
To inform the debate, we studied the relationship between various SAB positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft surviv...
Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valu...
Acute atherosis is an arterial lesion most often occurring in pregnancies complicated by preeclampsia, a hypertensive pregnancy disorder. Acute atherosis predominates in the maternal spiral arteries in the decidua basalis layer of the pregnant uterus. This layer forms the fetal-maternal immunological interface, where fetal extravillous trophoblasts...
Introduction: Highly sensitized patients awaiting a kidney transplant accrue on the transplant waiting list. The breadth of HLA antibodies in this subpopulation of patients precludes receiving a compatible organ offer through regular allocation within an acceptable time-frame.
Areas covered: Several alternative options to receive a transplant exist...
Background:
Antibodies directed against human leucocyte antigens (HLA) can develop through pregnancy, blood transfusions or organ transplants. Anecdotal evidence suggests that virus-specific antibodies may have the capacity to cross-react with HLA, a phenomenon called heterologous immunity, which is well described for T cell alloreactivity.
Metho...
Background:
Identification of specific HLA alleles and T cell epitopes that influence the course of BK polyomavirus (BKPyV) infection after kidney transplantation (KTx), including development of BKPyV-associated nephropathy (BKPyVAN), can be useful for patient risk stratification and possibly vaccine development.
Methods:
In a retrospective coho...
High expression levels of the calcium-binding proteins S100A8 and S100A9 in myeloid cells in kidney transplant rejections are associated with a favorable outcome. Here we investigated the myeloid cell subset expressing these molecules, and their function in inflammatory reactions. Different monocyte subsets were sorted from buffy coats of healthy d...
Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We cr...
For hematopoietic stem cell transplantation (HCT) HLA 10/10 (HLA-A, B, C, DRB1, DQB1) matched donors are optimal, but are not available for all patients. The identification of permissive/non-immunogenic mismatches may improve the outcome of HLA mismatched transplants. We hypothesize that HLA alleles identical within the antigen recognition domain (...
HLA antibodies are associated with refractoriness to platelet transfusion, leading to rapid platelet clearance, sometimes coinciding with clinical side effects such as fever and chills. The presence of HLA antibodies does not always present with clinical symptoms. It is currently unclear why refractoriness to platelet transfusion is only observed i...
Purpose of review:
Highly sensitized patients awaiting a renal transplant have a low chance of receiving an organ offer. Defining acceptable antigens and using this information for allocation purposes can vastly enhance transplantation of this subgroup of patients, which is the essence of the Eurotransplant Acceptable Mismatch program. Acceptable...
Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome-wide association studies (GWAS...
The presence of pre‐existing (memory) or de novo donor specific HLA antibodies (DSA) is a known barrier to successful long‐term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of ris...
Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) p...
The presence of donor‐specific anti‐HLA antibodies (DSA) is associated with increased risk of graft failure after kidney transplantation. We hypothesized that DSA against HLA class‐I, ‐II or both indicate a different risk for graft loss between deceased‐ and living‐donor transplantation. In this study we investigated the impact of pretransplant DSA...
Purpose:
Antitumor T cells need expression of HLA class I molecules but can be inhibited by ligands such as programmed death ligand 1 (PD-L1). We determined expression and regulation of these molecules in human conjunctival melanoma (CM) samples, cell lines, and murine xenografts.
Methods:
Immunofluorescence staining was performed to examine the...
HLA-G expressed by trophoblasts at the fetal-maternal interface and its soluble form have immunomodulatory effects. HLA-G expression depends on the combination of DNA polymorphisms. We hypothesized that combinations of specific single nucleotide polymorphisms (SNPs) in the 3′untranslated region (3′UTR) of HLA-G play a role in unexplained recurrent...
Background:
Molecules of the innate immune response are increasingly recognized as important mediators in allograft injury during and after kidney transplantation. We therefore aimed to establish the relationship between the expression of these genes at implantation, during an acute rejection (AR) and on graft outcome.
Methods:
A total of 19 gen...
