Biomedical subjects

Dave L Roelen

Publications and source records attributed to Dave L Roelen.

At least 19 recordsLinked to original sources

PubMed2026

A multicenter kidney transplantation study identifies hierarchy and directionality of HLA-DQ alloimmune responses.

HLA-incompatibility between recipient and donor is conventionally assessed by counting serologic mismatches. More recently, tools quantifying differences at the amino acid level are advocated to prognosticate risk for generation of de-novo donor-specific antibodies (dnDSA). Using hierarchical clustering based on HLA evolutionary divergence and amino acid physiochemical unique qualities to evaluate HLA-DQ αβ-heterodimers, we demonstrate that HLA-DQ alleles segregate into two main evolutionary clades, and further subdivide into six functional sub-categories. Applying this biologically grounded immune risk-stratification approach to a cohort of 3003 kidney allograft recipients from five transplant centers shows that transplantation across the two evolutionary clades is associated with hierarchy and directionality of humoral immune responses, despite similar values when applying quantitative metrics. Our three-tier risk stratification model identifies patients at higher risk to develop dnDSA (HR:6.77; 95%CI:4.64-9.90), and antibody mediated rejection (HR:4.41; 95%CI:1.44-13.53). This work provides a thoughtful immunologic framework, that outperforms quantitative metrics, for alloimmune risk stratification.

Humans↗

PubMed2025

Maternal-Foetal HLA-DQB1 Incompatibility Is Associated With Pregnancy-Induced Hypertensive Disorders in a Genetically Isolated Population.

In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (FROH 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4+ T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disorders. Nonetheless, maternal-foetal HLA-DQB1 mismatch seems to play a role in the aetiology of hypertensive complications during pregnancy in this population.

Humans↗

PubMed2006

The ratio of interferon-gamma and interleukin-10 producing donor-specific cells as an in vitro monitoring tool for renal transplant patients.

If in vitro tools can be used to predict which renal transplant patients are at risk for rejection and which patients are more predisposed to tolerance, the immunosuppressive regimen can be adjusted to prevent rejection before it becomes clinically apparent or, in case of a tolerant patient, medication can be reduced or even stopped. Peripheral blood mononuclear cells (PBMC) of patients with persistent stable graft function and of patients with (biopsy-confirmed) acute rejection were stimulated with donor cells and tested with Elispot analysis. A significantly higher number of donor-specific interferon (IFN)-gamma producing cells were found in patients with rejection, as determined with Elispot analysis. Furthermore, a trend towards a higher number of interleukin (IL)-10 producing cells was found in patients with stable graft function. The ratio of IFN-gamma/IL-10 producing cells showed to be the best tool to discriminate between nonrejecting patients and rejecting patients.

Adult↗

PubMed2006

Differential immunogenicity of HLA class I alloantigens for the humoral versus the cellular immune response: "towards tailor-made HLA mismatching".

The immunogenicity of an individual human leukocyte antigen (HLA) class I mismatch is different for the cellular and the humoral alloimmune responses. The consequence is that the same antigen can induce a strong antibody response and no cytotoxic T lymphocyte reactivity, but the reverse can occur also. Exact knowledge of the immunogenicity of an HLA mismatch for an individual patient can lead to a strategy of tailor-made HLA mismatching if no HLA identical donor is available. Depending on the clinical situation, one should select a donor with HLA mismatches according to the humoral or cellular mismatch algorithm.

Antibody Formation↗

PubMed2006

No in vitro evidence for a decreased alloreactivity toward noninherited maternal HLA antigens in healthy individuals.

Pre- and/or perinatal exposure to noninherited maternal HLA antigens (NIMA) is associated with a decreased HLA antibody formation against the NIMA and a significantly better graft survival of kidney grafts from siblings or those from unrelated donors who were mismatched for the NIMA haplotype compared with the NIPA (noninherited paternal HLA antigens) haplotype later in life. These observations suggest that some form of immunological tolerance against NIMA is induced. We analyzed the in vitro T cell reactivity of healthy individuals toward their parents and/or siblings expressing the NIMA or NIPA haplotype to explore whether the alloimmune response to NIMA has distinct characteristics compared with NIPA. No differences were detected by mixed lymphocyte reactions (MLR) and supernatants taken from the MLR showed no differences in IFN-gamma and IL-10 production. Additionally, no differences were found with IFN-gamma and IL-10 Elispot analyses. Phenotypic analysis revealed no selective increase in the number of CD3-CD8dim cells (thought to be a NK-like regulator cell) and the number of CD4+CD25+CD152+ cells (naturally occurring regulatory T cells) after stimulation with NIMA-expressing cells when compared with NIPA-expressing cells. In conclusion, no evidence of an influence of a NIMA effect on the cellular level was found in healthy individuals with "standard" immunological techniques.

Enzyme-Linked Immunosorbent Assay↗

PubMed2006

The influence of inherited and noninherited parental antigens on outcome after transplantation.

Contact between the immune systems of mother and child during pregnancy has an impact on transplantation later in life. Exposure to inherited paternal human leukocyte antigens (HLA) (IPA) and the noninherited maternal HLA antigens (NIMA) can lead to either immunization or tolerization. Exposure to IPA seems to have a more immunizing effect as the mature immune system of a mother can form anti-HLA antibodies against the foreign paternal HLA molecules. On the other hand, exposure of a child to the NIMA antigens during pregnancy may lead to NIMA-specific tolerance. This review provides an overview of the current knowledge on the impact of this fetal-maternal interaction on the alloimmune response and clinical transplantation.

Animals↗

PubMed2005

Allogeneic MHC class I molecules with numerous sequence differences do not elicit a CTL response.

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.

Amino Acid Substitution↗

PubMed2005

Alloreactivity against repeated HLA mismatches of sequential islet grafts transplanted in non-uremic type 1 diabetes patients.

BACKGROUND: Islet transplantation can restore insulin production in type 1 diabetes patients. However, survival of the islet allografts will face rejection or recurrence of autoimmunity or a combination of both. In a study on islet-after-kidney transplants, we previously reported that islet cell recipients presented low T-cell alloresponses for HLA mismatches that were shared by the islet cell graft and the prior kidney graft, that is, repeated mismatch, while vigorous responses were measured against novel HLA mismatches. METHODS: We now investigated T-cell alloreactivity to repeated HLA-mismatches in three non-uremic type 1 diabetic patients each receiving three sequential islet cell implants. RESULTS: These islet-after-islet recipients patients exhibited low or absent responses to repeated mismatches to the first graft which was accompanied by sustained graft function, and reduced responsiveness towards subsequent grafts. In one patient, T-cell responses towards these mismatches were noticed following new mismatches in subsequent grafts, with loss of graft function. CONCLUSION: These case reports further support the view that subsequent islet implantations can reduce alloreactivity for repeated HLA mismatches. They demonstrate the usefulness of monitoring T-cell reactivity against islet allografts to correlate immune function with graft survival and to identify conditions for preservation of beta-cell function.

Antilymphocyte Serum↗

PubMed2005

Differential immunogenicity of HLA mismatches in clinical transplantation.

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.

Algorithms↗

PubMed2005

The putative mechanism of the immunomodulating effect of HLA-DR shared allogeneic blood transfusions on the alloimmune response.

Pretransplant blood transfusions have shown to improve organ allograft survival. However, the immunologic mechanism leading to this beneficial effect in clinical transplantation is still not clear. The observation that blood transfusions sharing an HLA-DR antigen with the recipient are more effective than HLA mismatched transfusions has led to the hypothesis that CD4(+) regulatory T (Treg) cells that recognize a foreign peptide in the context of the shared HLA-DR molecule play an important role in down-regulation of the immune response toward the graft. Available experimental evidence supports this hypothesis. Furthermore, these CD4(+) Treg cells are able to modulate antigen-presenting cells, which in their turn will induce Treg cells. As long as clinical transplantation tolerance by blood transfusions is not a reality, further studies on the mechanisms of the beneficial effect of pretransplant allogeneic blood transfusions are needed to obtain an effective protocol for the induction of clinically relevant Treg cells.

Blood Transfusion↗

PubMed2004

HLAMatchmaker algorithm is not a suitable tool to predict the alloreactive cytotoxic T-lymphocyte response in vitro.

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.

Algorithms↗

PubMed2004

The number of amino acid triplet differences between patient and donor is predictive for the antibody reactivity against mismatched human leukocyte antigens.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Amino Acid Sequence↗

PubMed2004

The immunologic profile of infants born after maternal immunoglobulin treatment and intrauterine platelet transfusions for fetal/neonatal alloimmune thrombocytopenia.

OBJECTIVE: The purpose of this study was to evaluate whether maternally administered intravenous immunoglobulins (IVIG) and intrauterine platelet transfusions (IUPT) for fetal/neonatal alloimmune thrombocytopenia (FNAIT) affect the development of the fetal immune system. STUDY DESIGN: The lymphocyte subset distribution of mononuclear cells of cord blood of 20 FNAIT newborns was analyzed by flow cytometry and compared with a control group of healthy newborns and a reference group treated with intrauterine erythrocyte transfusions (IUET) for hemolytic disease. RESULTS: The percentage of monocytes, natural killer (NK) cells, ratios of mature and immature T cells and B cells, and resting or activated cells were not significantly different compared to the control group. In addition, the B-cell and T-cell populations showed a normal in vitro antibody production and T-cell proliferation when compared with the control group. CONCLUSION: Antenatal treatment for FNAIT with maternal IVIG with or without IUPT is not associated with lymphocyte activation or premature maturation of the neonatal immune system.

B-Lymphocytes↗

PubMed2004

The HLA-DR phenotype of the responder is predictive of humoral response against HLA class I antigens.

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.

Antibody Formation↗

PubMed2004

Comparison of decidual leukocytes following spontaneous vaginal delivery and elective cesarean section in uncomplicated human term pregnancy.

The aim of this study was to quantify and compare leukocyte populations in term decidua basalis and parietalis obtained after spontaneous vaginal delivery (SVD) or elective cesarean section (CS) without labor. Decidua basalis and parietalis samples were obtained from placentas after SVD (n = 20) and after CS (n = 30). Following mechanical disaggregation, leukocytes were purified and stained with monoclonal antibodies. Percentages of leukocyte subclasses within the CD45(+) cell fraction and activated T cells were determined by flow cytometry. No differences were found in the percentages of CD45(+) cells or CD56(bright)CD16(-) uterine natural killer (NK) cells between decidua basalis from SVD and CS or between decidua parietalis from SVD and CS. In decidua basalis and parietalis from SVD, a significantly higher number of CD56(dim)CD16(+) NK cells was found compared to CS. In decidua basalis from SVD, there was a significantly lower percentage of CD14(+) cells and higher percentage of CD19(+) cells compared to CS. The percentage of CD3(+) T cells expressing CD25 or human leukocyte antigen (HLA)-DR was significantly decreased in decidua basalis and parietalis from SVD compared to CS. Comparison of decidua collected after SVD or CS suggests that labor is associated with dynamic changes in the distribution of decidual leukocytes, specifically NK and T cell subpopulations. In particular, the disappearance of the CD4(+)CD25(+) T cell population, which possibly contains a subpopulation of regulatory T cells, may contribute to the initiation of labor. Further investigation into factors affecting decidual leukocytes may expand our understanding of the immunological events at the maternal-fetal interface.

Antigens, CD↗

PubMed2003

Prolongation of skin graft survival by modulation of the alloimmune response with alternatively activated dendritic cells.

BACKGROUND: Activation of immature dendritic cells (DC) in the presence of the glucocorticoid hormone dexamethasone (DEX) results in alternatively matured DC that present antigen in the absence of a proper co-stimulatory context. This maturation process is irreversible, making these cells an attractive potential tool for the induction of antigen-specific T-cell tolerance in vivo. The authors explored the possibility of using these DC for the induction of transplantation tolerance in a fully allogeneic setting in mice. METHODS: Immature dendritic cells (D1, an immature splenic DC line derived from B6 mice) were pretreated with DEX for 24 hr, after which lipopolysaccharide or nothing was added to the culture for another 48 hr. These cells were analyzed for their in vitro and in vivo stimulating or tolerizing capacities. RESULTS: In line with their phenotype, including decreased interleukin (IL)-12 production, in vitro co-culture of alternatively matured D1 (B6 origin; H-2b) with completely allogeneic T cells of BALB/c origin led to a significant decrease in the alloreactive T-cell response. A single injection of 1 x 10(6) alternatively matured H-2b DC into BALB/c mice induced a different alloimmune response compared with mature DC. The responding T cells showed a lower proliferation rate and a lower interferon-gamma production, whereas a significantly higher proportion of the cells produced IL-10 as measured ex vivo by enzyme-linked immunospot assay. Furthermore, injection with alternatively matured DC, followed by transplantation of fully mismatched skin grafts (C57BL/6), led to a significantly prolonged survival compared with that of mature DC-pretreated mice or untreated mice. The immunomodulatory effect was antigen specific, as third-party reactive alloresponses were not affected. CONCLUSIONS: The authors' data constitute the first direct demonstration that DC alternatively matured in the presence of glucocorticoid hormones can be exploited for the specific suppression of the alloreactive Th1 response, resulting in a delayed skin graft rejection in a complete major histocompatibility complex-incompatible strain combination.

Animals↗

PubMed2003

Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28.

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.

Antibodies↗

PubMed2003

Differential immunogenicity of paternal HLA Class I antigens in pregnant women.

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.

Female↗