27 results on '"Kwekkeboom, Jaap"'
Search Results
2. Intrahepatic CD8 + T-lymphocyte response is important for therapy-induced viral clearance in chronic hepatitis B infection
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Tang, Thjon J., Kwekkeboom, Jaap, Mancham, Shanta, Binda, Rekha S., de Man, Robert A., Schalm, Solko W., Kusters, Johannes G., and Janssen, Harry L.A.
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- 2005
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3. Blockade of intragraft IL-2 receptor-α by basiliximab is insufficient to prevent activation of liver graft infiltrating cells
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Kwekkeboom, Jaap, Warlé, Michiel C., Rietveld, John, Segeren, Katja C.A., Tilanus, Hugo W., and Metselaar, Herold J.
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- 2003
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4. Cross-Tissue Transcriptomic Analysis of Human Secondary Lymphoid Organ-Residing ILC3s Reveals a Quiescent State in the Absence of Inflammation.
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Bar-Ephraim, Yotam E., Cornelissen, Ferry, Papazian, Natalie, Konijn, Tanja, Hoogenboezem, Remco M., Sanders, Mathijs A., Westerman, Bart A., Gönültas, Mehmet, Kwekkeboom, Jaap, Den Haan, Joke M.M., Reijmers, Rogier M., Mebius, Reina E., and Cupedo, Tom
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Summary A substantial number of human and mouse group 3 innate lymphoid cells (ILC3s) reside in secondary lymphoid organs, yet the phenotype and function of these ILC3s is incompletely understood. Here, we employed an unbiased cross-tissue transcriptomic approach to compare human ILC3s from non-inflamed lymph nodes and spleen to their phenotypic counterparts in inflamed tonsils and from circulation. These analyses revealed that, in the absence of inflammation, lymphoid organ-residing ILC3s lack transcription of cytokines associated with classical ILC3 functions. This was independent of expression of the natural cytotoxicity receptor NKp44. However, and in contrast to ILC3s from peripheral blood, lymphoid organ-residing ILC3s express activating cytokine receptors and have acquired the ability to be recruited into immune responses by inflammatory cytokines. This comprehensive cross-tissue dataset will allow for identification of functional changes in human lymphoid organ ILC3s associated with human disease. [ABSTRACT FROM AUTHOR]
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- 2017
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5. Dynamics of Proliferative and Quiescent Stem Cells in Liver Homeostasis and Injury.
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Cao, Wanlu, Chen, Kan, Bolkestein, Michiel, Yin, Yuebang, Verstegen, Monique M.A., Bijvelds, Marcel J.C., Wang, Wenshi, Tuysuz, Nesrin, ten Berge, Derk, Sprengers, Dave, Metselaar, Herold J., van der Laan, Luc J.W., Kwekkeboom, Jaap, Smits, Ron, Peppelenbosch, Maikel P., and Pan, Qiuwei
- Abstract
Background & Aims Adult liver stem cells are usually maintained in a quiescent/slow-cycling state. However, a proliferative population, marked by leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), was recently identified as an important liver stem cell population. We aimed to investigate the dynamics and functions of proliferative and quiescent stem cells in healthy and injured livers. Methods We studied LGR5-positive stem cells using diphtheria toxin receptor and green fluorescent protein (GFP) knock-in mice. In these mice, LGR5-positive cells specifically coexpress diphtheria toxin receptor and the GFP reporter. Lineage-tracing experiments were performed in mice in which LGR5-positive stem cells and their daughter cells expressed a yellow fluorescent protein/mTmG reporter. Slow-cycling stem cells were investigated using GFP-based, Tet-on controlled transgenic mice. We studied the dynamics of both stem cell populations during liver homeostasis and injury induced by carbon tetrachloride. Stem cells were isolated from mouse liver and organoid formation assays were performed. We analyzed hepatocyte and cholangiocyte lineage differentiation in cultured organoids. Results We did not detect LGR5-expressing stem cells in livers of mice at any stage of a lifespan, but only following liver injury induced by carbon tetrachloride. In the liver stem cell niche, where the proliferating LGR5 + cells are located, we identified a quiescent/slow-cycling cell population, called label-retaining cells (LRCs). These cells were present in the homeostatic liver, capable of retaining the GFP label over 1 year, and expressed a panel of progenitor/stem cell markers. Isolated single LRCs were capable of forming organoids that could be carried in culture, expanded for months, and differentiated into hepatocyte and cholangiocyte lineages in vitro, demonstrating their bona fide stem cell properties. More interestingly, LRCs responded to liver injury and gave rise to LGR5-expressing stem cells, as well as other potential progenitor/stem cell populations, including SOX9- and CD44-positive cells. Conclusions Proliferative LGR5 cells are an intermediate stem cell population in the liver that emerge only during tissue injury. In contrast, LRCs are quiescent stem cells that are present in homeostatic liver, respond to tissue injury, and can give rise to LGR5 stem cells, as well as SOX9- and CD44-positive cells. [ABSTRACT FROM AUTHOR]
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- 2017
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6. JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa.
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Boor, Patrick P.C., de Ruiter, Petra E., Asmawidjaja, Patrick S., Lubberts, Erik, van der Laan, Luc J.W., and Kwekkeboom, Jaap
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Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using in vitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment. [ABSTRACT FROM AUTHOR]
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- 2017
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7. Disturbance of the microRNA pathway by commonly used lentiviral shRNA libraries limits the application for screening host factors involved in hepatitis C virus infection
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Pan, Qiuwei, de Ruiter, Petra E., von Eije, Karin J., Smits, Ron, Kwekkeboom, Jaap, Tilanus, Hugo W., Berkhout, Ben, Janssen, Harry L.A., and van der Laan, Luc J.W.
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- 2011
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8. Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection.
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van Gent, Rogier, Metselaar, Herold J., and Kwekkeboom, Jaap
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Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of ‘direct’ anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT. [ABSTRACT FROM AUTHOR]
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- 2017
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9. Rotterdam: Main port for organ transplantation research in the Netherlands.
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Kwekkeboom, Jaap, van der Laan, J. W., Betjes, Michiel G. H., Manintveld, Olivier C., Hoek, Rogier A. S., Cransberg, Karlien, de Bruin, Ron W. F., Dor, Frank J. M. F., de Jonge, Jeroen, Boor, Patrick P. C., van Gent, Rogier, van Besouw, Nicole M., Boer, Karin, Litjens, Nicolle H. R., Hesselink, Dennis A., Hoogduijn, Martin J., Massey, Emma, Rowshani, Ajda T., van de Wetering, Jacqueline, and de Jong, Huib
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TRANSPLANTATION of organs, tissues, etc. , *ACADEMIC medical centers , *ORGAN donation , *IMMUNOSUPPRESSIVE agents , *REPERFUSION injury , *REGENERATION (Biology) , *MEDICAL care - Abstract
This overview describes the full spectrum of current pre-clinical and clinical kidney-, liver-, heart- and lung transplantation research performed in Erasmus MC - University Medical Centre in Rotterdam, The Netherlands. An update is provided on the development of a large living donor kidney transplantation program and on optimization of kidney allocation, including the implementation of a domino kidney-donation program. Our current research efforts to optimize immunosuppressive regimens and find novel targets for immunosuppressive therapy, our recent studies on prevention of ischemia-reperfusion-induced graft injury, our newest findings on stimulation of tissue regeneration, our novel approaches to prevent rejection and viral infection, and our latest insights in the regulation of allograft rejection, are summarized. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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10. Prevention of immunoglobulin G immobilization eliminates artifactual stimulation of dendritic cell maturation by intravenous immunoglobulin in vitro.
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Tjon, Angela S.W., Jaadar, Haziz, van Gent, Rogier, van Kooten, Peter J.S., Achatbi, Najib, Metselaar, Herold J., and Kwekkeboom, Jaap
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Intravenous immunoglobulin (IVIg), a therapeutic preparation containing pooled human immunoglobulin (Ig) G, has been suggested to inhibit differentiation and maturation of dendritic cells (DCs); however, controversies exist on this issue. We aimed to reinvestigate the effects of IVIg on human DC maturation and cytokine production, and to determine whether an artifactual determinant is involved in the observed effects. Human monocyte-derived DCs or freshly isolated blood myeloid DCs were cultured in the presence of IVIg in vitro, and the expression of maturation markers CD80, CD86, CD83, and Human Leukocyte Antigen-DR were determined by flow cytometry, whereas production of interleukin (IL)-12 and IL-10 was measured by enzyme-linked immunosorbent assay, and T-cell stimulatory capacity was determined in cocultures with allogeneic CD4
+ T cells. Interestingly, we observed that IVIg did not inhibit, but instead stimulated, spontaneous maturation and T-cell stimulatory ability of human DCs, while leaving lipopolysaccharide-induced DC maturation and cytokine production unaffected. Strikingly, prevention of IVIg binding to culture plate surface, or blocking of the activating Fcγ receptor IIa on DC, abrogated the stimulatory effect of IVIg on costimulatory molecule expression and on T-cell stimulatory capacity of DCs, suggesting that IVIg activates DCs on IgG adsorption to the plastic surface. This study warrants for careful study design when performing cell culture studies with IVIg to prevent artifactual effects, and shows that IVIg does not modulate directly costimulatory molecule expression, cytokine production, or allogeneic T-cell stimulatory capacity of human DCs. [ABSTRACT FROM AUTHOR]- Published
- 2014
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11. Aberrant composition of the dendritic cell population in hepatic lymph nodes of patients with hepatocellular carcinoma.
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Tang, Thjon J., Vukosavljevic, Dragica, Janssen, Harry L.A., Binda, Rekha S., Mancham, Shanta, Tilanus, Hugo W., IJzermans, Jan N.M., Drexhage, Hemmo, and Kwekkeboom, Jaap
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CANCER patients ,HEPATITIS C ,HEPATITIS C virus ,CELL proliferation - Abstract
Summary: Patients with hepatocellular carcinoma (HCC) are characterized by a weak T-cell response to their tumor, and chronic carriers of hepatitis B virus or hepatitis C virus have a poor T-cell response against the virus. These inadequate T-cell responses may be due to insufficient activation of the T cells by dendritic cells (DCs). Because lymph nodes (LNs) are the primary site of antigen-specific T-cell activation, we hypothesized that hepatic LNs of patients with HCC and/or chronic viral hepatitis might have aberrant compositions of their DC populations. To address this hypothesis, we enumerated mature myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in hepatic LNs by quantitative immunohistochemistry. Patients with HCC and chronic viral hepatitis and patients with chronic viral hepatitis without HCC were compared with patients with liver inflammation of nonviral etiology and with organ donors with healthy livers. The numbers of PDCs and mature MDCs in hepatic LNs of patients with chronic viral hepatitis did not differ from those of patients with liver inflammation of nonviral etiology nor from individuals with healthy livers. However, hepatic LNs of patients with HBV or HCV infection complicated by HCC showed a 1.5-fold reduction in numbers of mature MDCs and a 4-fold increase in numbers of PDCs in their T-cell areas compared with those of patients with viral hepatitis only (P < .01). In conclusion, patients with HCC have an aberrant composition of the DC population in their hepatic LNs. This may be one of the causes of the inadequate T-cell response against HCC in these patients. [Copyright &y& Elsevier]
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- 2006
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12. Intrahepatic CD8+ T-lymphocyte response is important for therapy-induced viral clearance in chronic hepatitis B infection
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Tang, Thjon J., Kwekkeboom, Jaap, Mancham, Shanta, Binda, Rekha S., de Man, Robert A., Schalm, Solko W., Kusters, Johannes G., and Janssen, Harry L.A.
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CD antigens , *T cells , *THERAPEUTICS , *HEPATITIS B - Abstract
Background/Aims: To determine which immune cells contribute to HBV-clearance during antiviral therapy, we performed a longitudinal analysis of intrahepatic immune cells during interferon-α therapy of chronic HBV-patients using the FNAB technique. Methods: Twenty chronic HBeAg+-patients were treated with pegylated α-interferon combined with lamivudine or placebo for 52 weeks. FNAB and blood specimens were obtained at week 0, 2, 8 and 52. CD4+- and CD8+ T-lymphocytes, CD56+ cells, IFNγ and granzyme B (GrB) were immunocytochemically quantified. Results: The relative numbers of CD56+ cells and CD8+ T-lymphocytes were significantly higher in FNAB compared to blood at all time-points. Responders (n=9) exhibited significant increases in intrahepatic CD8+ and CD8+GrB+ lymphocytes, a small elevation in CD8+IFNγ+ T-lymphocytes, no change in CD4+ T-lymphocytes, and a decrease in intrahepatic CD56+ cells during the first weeks of therapy. In non-responders (n=11) no significant changes in CD4+- and CD8+ T-lymphocytes and an increase in intrahepatic and CD56+ cells were observed during therapy. Conclusions: The intrahepatic CD8+ T-lymphocyte, but not the CD4+ T-lymphocyte or NK/NKT-cell response, is important for HBV clearance during interferon-α therapy, and the antiviral effect may be mediated by both cytolytic and non-cytolytic mechanisms. [Copyright &y& Elsevier]
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- 2005
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13. Basiliximab interferes with the detection of soluble IL-2 receptor by the Immulite Immunoassay system
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Warlé, Michiel C., Kwekkeboom, Jaap, Tilanus, Hugo W., and Metselaar, Herold J.
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INTERLEUKIN-2 , *MONOCLONAL antibodies - Abstract
The use of the Immulite Automated Immunoassay system is becoming an increasingly popular method for accurate and fast measurement of sIL-2R in serum. Here, we report that detection of sIL-2R using the Immulite Immunoassay system in serum samples of patients who are treated with basiliximab, a monoclonal antibody against the alpha-chain of the IL-2 receptor, may lead to false measurements. [Copyright &y& Elsevier]
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- 2003
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14. Observed differences in the tumour microenvironment provide a potential explanation for the superior survival of patients with desmoplastic colorectal liver metastasis.
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Höppener, Diederik, Nierop, Pieter, Hof, Joost, Sideras, Kostas, Zhou, Guoying, de Jong, Koert, Sprengers, Dave, Kwekkeboom, Jaap, Vermeulen, Peter, Grünhagen, Dirk, and Verhoef, Cornelis
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LIVER metastasis ,TUMORS - Abstract
B Background: b Patients with resected colorectal liver metastasis (CRLM) that display only angiogenic desmoplastic growth (dHGP) exhibit better survival compared to patients with any observed non-desmoplastic growth (non-dHGP). This study aims to compare the tumour microenvironment (TME) of patients with dHGP and non-dHGP. [Extracted from the article]
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- 2020
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15. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.
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Zhou, Guoying, Sprengers, Dave, Boor, Patrick P.C., Doukas, Michail, Schutz, Hannah, Mancham, Shanta, Pedroza-Gonzalez, Alexander, Polak, Wojciech G., de Jonge, Jeroen, Gaspersz, Marcia, Dong, Haidong, Thielemans, Kris, Pan, Qiuwei, IJzermans, Jan N.M., Bruno, Marco J., and Kwekkeboom, Jaap
- Abstract
Background & Aims Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell–mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non–small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. Methods We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Results Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. Conclusions The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. [ABSTRACT FROM AUTHOR]
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- 2017
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16. Mo1033 Tumor Antigen Expression Differs in Hepatocellular Carcinoma (HCC) Between Viral Hepatitis and Non-Viral Hepatitis Patients.
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Sideras, Kostandinos, Bots, Steven, Polak, Wojciech G., Ijzermans, Jan N., Sprengers, Dave, Sleijfer, Stefan, Biermann, Katharina, Bruno, Marco J., and Kwekkeboom, Jaap
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- 2014
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17. Minimal Development of Liver Fibrosis in Adult Tolerant Liver Transplant Recipients Late After Immunosuppressive Drug Weaning and Transplantation.
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Duizendstra, Aafke A., De Knegt, Robert J., Nagtzaam, Nicole M.A., Betjes, Michiel G.H., Dik, Willem A., Litjens, Nicolle H.R., and Kwekkeboom, Jaap
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HEPATIC fibrosis , *LIVER transplantation , *IMMUNOSUPPRESSIVE agents , *BIOMARKERS , *MEDICAL ethics committees - Abstract
Operationally tolerant liver transplant (LTx)-recipients can be weaned off immunosuppressive (IS) drugs without development of graft rejection. However, it is feared that liver fibrosis might develop after complete IS weaning. The purpose of this small single-center study was to assess liver fibrosis in adult tolerant LTx recipients long after LTx and IS weaning. Liver fibrosis was assessed in adult tolerant LTx-recipients (n = 9) using noninvasive transient elastography and measurements of multiple pro- and antifibrotic serum markers associated with liver fibrosis. The data was collected for 2 subsequent years; 8 and 9 years after IS weaning and 19 and 20 years after transplantation. Healthy individuals (n = 9) matched for age and sex were included as a reference for fibrosis-related serum markers. This study was conducted in accordance with the Declaration of Helsinki and approved by the medical ethics committee of our institution. Transient elastography indicated that 7 of 9 tolerant LTx recipients had no or minimal liver fibrosis (F0-F1), whereas 2 recipients had moderate or severe liver fibrosis (F2-F3). Most fibrosis-related serum markers in tolerant LTx recipients were within or close to the range obtained for healthy individuals. The results from this small, single-center study indicated that most adult tolerant LTx recipients have no or minimal liver graft fibrosis long after transplantation and IS weaning, and their fibrosis-related serum marker profile indicates an absence of a profibrotic status. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction.
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Shi, Xiao-Lei, Mancham, Shanta, Hansen, Bettina E., de Knegt, Robert J., de Jonge, Jeroen, van der Laan, Luc J.W., Rivadeneira, Fernando, Metselaar, Herold J., and Kwekkeboom, Jaap
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LIVER transplantation , *GRAFT rejection , *LEUCOCYTES , *SINGLE nucleotide polymorphisms , *IMMUNOHISTOCHEMISTRY - Abstract
Background & Aims Co-inhibitory receptor-ligand interactions fine-tune immune responses by negatively regulating T cell functions. Our aim is to examine the involvement of co-inhibitory receptor-ligand pair PD-1/PD-L1 in regulating rejection after liver transplantation (LT) in humans. Methods PD-L1/PD-1 expression in liver allograft was determined by immunohistochemistry or flow cytometry, and the effect of blockade was studied using graft-infiltrating T cells ex vivo . Five single nucleotide polymorphisms within PD-1 and PD-L1 genes were genotyped in 528 LT recipients and 410 donors, and associations with both early (⩽6 months) and late (>6 months) acute rejection were analyzed using Cox proportional-hazards regression model. The effect of PD-L1 rs4143815 on PD-L1 expression was analyzed using donor hepatic leukocytes. Results PD-L1 was expressed by hepatocytes, cholangiocytes and along the sinusoids in post-transplant liver allografts, and PD-1 was abundantly expressed on allograft-infiltrating T cells. PD-L1 blockade enhanced allogeneic proliferative responses of graft-infiltrating T cells. In the genetic association analysis, donor PD-L1 rs4143815 (CC/CG vs. GG; HR = 0.230; p = 0.002) and recipient PD-1 rs11568821 (AA/AG vs. GG; HR = 3.739; p = 0.004) were associated with acute rejection late after LT in multivariate analysis. Recipients carrying the PD-1 rs11568821 A allele who were transplanted with liver grafts of PD-L1 rs4143815 GG homozygous donors showed the highest risk for late acute rejection. PD-L1 rs4143815 is associated with differential PD-L1 expression on donor hepatic dendritic cells upon IFN-γ stimulation. Conclusion Our data suggest that interplay between donor PD-L1 and recipient PD-1 counter-regulates rejection activity against liver grafts in humans. [ABSTRACT FROM AUTHOR]
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- 2016
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19. Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation.
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Senkerikova, Renata, de Mare-Bredemeijer, Emmeloes, Frankova, Sona, Roelen, Dave, Visseren, Thijmen, Trunecka, Pavel, Spicak, Julius, Metselaar, Herold, Jirsa, Milan, Kwekkeboom, Jaap, and Sperl, Jan
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HUMAN genetic variation , *TUMOR necrosis factor receptors , *BACTERIAL diseases , *LIVER diseases , *LIVER transplantation , *TOLL-like receptors - Abstract
Background & Aims: Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). We sought to determine the contribution of selected genetic variants involved in inflammatory signalling downstream of the Toll-like receptor 4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD. Methods: We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.−159C/T, TNFA c.−238G/A, TNFA c.−863C/A, IL1B c.−31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated in an independent cohort of 332 ESLD patients. Results: Thirty-four percent of patients from the identification cohort and 40% of patients from the validation cohort presented with SBI while enlisted for OLT. The presence of the variant allele TNFA c.−238A (rs361525) was associated with lower serum levels of TNF-α, and with significantly decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative protection from SBI associated with this allele almost completely negated the increased susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality, the presence of the TNFA c.−238A allele was associated with a complete prevention of SBI-related pre-transplant deaths. Conclusions: Our results suggest that genetic variability in inflammatory signalling is associated with the development of SBI in patients with ESLD. Specifically, we identified the importance of the TNFA c.−238A allele as a strong predictor of protection from SBI, and as a genetic marker associated with significantly improved pre-transplant survival in patients with SBI. [Copyright &y& Elsevier]
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- 2014
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20. MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation.
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Verhoeven, Cornelia J., Farid, Waqar R.R., de Ruiter, Petra E., Hansen, Bettina E., Roest, Henk P., de Jonge, Jeroen, Kwekkeboom, Jaap, Metselaar, Herold J., Tilanus, Hugo W., Kazemier, Geert, and van der Laan, Luc J.W.
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BILE duct diseases , *MICRORNA , *LIVER transplantation , *PATHOLOGICAL physiology , *GRAFT rejection , *HEPATOCYTE growth factor , *DISEASE risk factors - Abstract
Background & Aims: Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though the exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive of the development of ITBL after liver transplantation. Methods: Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222, and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared. Results: MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (p <0.01) and were identified as an independent risk factor by multivariate analysis (p <0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; p ⩽0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies). Conclusions: This study demonstrates that differential release of CDmiRs during graft preservation is predictive of the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL. [Copyright &y& Elsevier]
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- 2013
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21. Modulation of the cellular immune system by intravenous immunoglobulin
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Tha-In, Thanyalak, Bayry, Jagadeesh, Metselaar, Herold J., Kaveri, Srini V., and Kwekkeboom, Jaap
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CELLULAR immunity , *IMMUNE system , *IMMUNOGLOBULIN G , *NATURAL immunity , *AUTOIMMUNE diseases , *INFLAMMATION - Abstract
Intravenous immunoglobulin (IVIg) is therapeutically used in a variety of immune-mediated diseases. The beneficial effects of IVIg in auto-antibody-mediated diseases can be explained by neutralization, accelerated clearance and prevention of Fcγ-receptor binding of auto-antibodies. However, the means by which IVIg exerts therapeutic effects in disorders mediated by cellular immunity have remained enigmatic. Clinical improvements, followed by IVIg treatment, often extend beyond the half-life of infused IgG, thereby indicating that IVIg modifies the cellular immune compartment for a prolonged period. Here, we discuss recent advances in the understanding of different, mutually non-exclusive mechanisms of action of IVIg on cells of the innate and adaptive immune system. These mechanisms might explain the beneficial effects of IVIg in certain autoimmune and inflammatory diseases. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
22. FRI488 - Modelling liver tumor organoids and cancer-associated fibroblasts interaction reveals the robust effects of stromal niche in cancer nurturing and treatment resistance.
- Author
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Liu, Jiaye, Li, Pengfei, Wang, Ling, Li, Meng, Ge, Zhouhong, Noordam, Lisanne, Lieshout, Ruby, Verstegen, Monique M.A., Ma, Buyun, Su, Junhong, Sprengers, Dave, Zhang, Ruyi, Zhou, Guoying, Smits, Ron, Kwekkeboom, Jaap, van der Laan, Luc J.W., Peppelenbosch, Maikel, Pan, Qiuwei, and Cao, Wanlu
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LIVER cancer , *ORGANOIDS , *CANCER treatment - Published
- 2020
- Full Text
- View/download PDF
23. AS049 - Identification of a panel of safe immunogenic antigens for therapeutic vaccination strategies in hepatocellular carcinoma.
- Author
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Noordam, Lisanne, Ge, Zhouhong, Öztürk, Hadiye, Mancham, Shanta, Doukas, Michael, Boor, Patrick, Zhou, Guoying, Vögler, Isabel, Pan, Qiuwei, IJzermans, Jan, Bruno, Marco J., Sprengers, Dave, and Kwekkeboom, Jaap
- Subjects
- *
HEPATOCELLULAR carcinoma , *ANTIGENS , *VACCINATION , *IDENTIFICATION - Published
- 2020
- Full Text
- View/download PDF
24. Immunomagnetic selection of functional dendritic cells from human lymph nodes
- Author
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Boor, Patrick P.C., IJzermans, Jan N.M., Molen, Renate G. van der, Binda, Rekha, Mancham, Shanta, Metselaar, Herold J., Kusters, Johannes G., Jong, Esther de, Drexhage, Hemmo A., and Kwekkeboom, Jaap
- Subjects
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DENDRITIC cells , *ANTIGEN presenting cells , *ANTIVIRAL agents , *CELL proliferation - Abstract
Abstract: It was investigated whether positive immunomagnetic selection with two novel DC-specific mAb allowed purification of functional myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC) from the human lymph nodes (LN). The results were compared with enrichment of DC by low-density Nycodenz gradient centrifugation followed by immunomagnetic depletion of residual B- and T-cells (Nycodenz method). MDC were selected from inguinal LN cell suspensions using CD1c mAb and PDC using anti-BDCA-4 mAb. Immunomagnetic selection with anti-CD1c mAb yielded highly pure MDC preparations (90±3% MDC; n =7), provided that the B-cells were thoroughly depleted by using CD19 magnetic beads and Large Depletion (LD) columns prior to selection of MDC. The purified MDC comprised both mature and immature cells and were functional, secreting large amounts of cytokines upon stimulation and strongly stimulating allogeneic T-cell proliferation. Immunomagnetic selection with anti-BDCA-4 mAb enriched PDC 70-fold to a purity of 59±26% (n =8). The contamination consisted mainly of BDCA-4+ T- and NK-cells. The previously used Nycodenz method yielded mixtures of MDC and PDC, not allowing functional studies of MDC and PDC separately. In conclusion, positive immunomagnetic selection with CD1c mAb from human LN cell suspensions yields almost pure MDC preparations, which are, in contrast to those obtained by the Nycodenz method, not contaminated with PDC. Moreover, these MDC are functionally intact. Selection with anti-BDCA-4 mAb does enrich PDC from human LN, but the resulting preparations are contaminated with T- and NK-cells. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
25. T-cell inhibitory capacity of hyperimmunoglobulins is influenced by the production process.
- Author
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van Gent, Rogier, Jaadar, Haziz, Tjon, Angela S.W., Mancham, Shanta, and Kwekkeboom, Jaap
- Subjects
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T cells , *IMMUNOGLOBULINS , *ANTI-inflammatory agents , *AUTOIMMUNE diseases , *IMMUNOREGULATION , *CYTOKINES - Abstract
Intravenous immunoglobulin (IVIg) preparations are widely used for anti-inflammatory therapy of autoimmune and systemic inflammatory diseases. Hyperimmunoglobulins enriched in neutralizing antibodies against viruses can, in addition to their virus-neutralizing activity, also exert immunomodulatory activity. Previously, we observed that Cytotect®, an anti-CMV hyperimmunoglobulin, was less effective in suppressing human T-cell responses in vitro compared to Hepatect® CP, an anti-HBV hyperimmunoglobulin. We hypothesized that the poor immunomodulatory activity of Cytotect® results from treatment with β-propiolactone during the manufacturing process. The manufacturer of these hyperimmunoglobulins has now introduced a new anti-CMV hyperimmunoglobulin, called Cytotect® CP, in which β-propiolactone treatment is omitted. Here we show that Cytotect® CP inhibits PHA-driven T-cell proliferation and cytokine production with similar efficacy as Hepatect® CP, whereas the former Cytotect® does not. In addition, Cytotect® CP inhibits allogeneic T-cell responses better than Cytotect®. Our results advocate the use of hyperimmunoglobulins that have not been exposed to β-propiolactone in order to benefit from their immunomodulatory properties. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
26. FRI484 - TIGIT and PD1 dual checkpoint blockade restores functionality of tumor-infiltrating T cells in hepatocellular carcinoma.
- Author
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Ge, Zhouhong, Zhou, Guoying, Carrascosa, Lucia Campos, Gausvik, Erik, Boor, Patrick, Noordam, Lisanne, Pan, Qiuwei, Verheij, Joanne, Erdmann, Joris, Doukas, Michael, IJzermans, Jan, Kraan, Jaco, Peppelenbosch, Maikel, Kwekkeboom, Jaap, and Sprengers, Dave
- Subjects
- *
T cells - Published
- 2020
- Full Text
- View/download PDF
27. Addendum to “MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation” [J Hepatol 2013;59:1231–1238].
- Author
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Verhoeven, Cornelia J., Selten, Jasmijn W., Roest, Henk P., Farid, Waqar R.R., de Ruiter, Petra E., Hansen, Bettina E., de Jonge, Jeroen, Kwekkeboom, Jaap, Metselaar, Herold J., Tilanus, Hugo W., Kazemier, Geert, IJzermans, Jan N.M., and van der Laan, Luc J.W.
- Subjects
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LIVER transplantation , *ISCHEMIA , *MICRORNA - Abstract
A correction to the article "MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation," which appeared in a previous issue of the periodical, is presented.
- Published
- 2017
- Full Text
- View/download PDF
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