Utrecht, Netherlands
Utrecht, Netherlands

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PubMed | Transplantation Center, Infectious Diseases Service, Clinic of Internal Medicine and Infectious Diseases, University of Lausanne and 6 more.
Type: Journal Article | Journal: The Journal of infectious diseases | Year: 2015

Polymorphisms in IFNL3 and IFNL4, the genes encoding interferon 3 and interferon 4, respectively, have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid-organ transplant recipients.White patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated.A total of 840 solid-organ transplant recipients at risk for CMV infection were included, among whom 373 (44%) received antiviral prophylaxis. The 12-month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR], 1.30 [95% confidence interval {CI}, .97-1.74]; P = .07), compared with other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR, 1.46 [95% CI, 1.01-2.12]; P = .047), especially in patients receiving an organ from a seropositive donor (SHR, 1.92 [95% CI, 1.30-2.85]; P = .001), but not among those who received antiviral prophylaxis (SHR, 1.13 [95% CI, .70-1.83]; P = .6). These associations remained significant in multivariate competing risk regression models.Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis.


Boross P.,Immunotherapy Laboratory | Lohse S.,University of Kiel | Nederend M.,Immunotherapy Laboratory | Jansen J.H.M.,Immunotherapy Laboratory | And 13 more authors.
EMBO Molecular Medicine | Year: 2013

Currently all approved anti-cancer therapeutic monoclonal antibodies (mAbs) are of the IgG isotype, which rely on Fcgamma receptors (FcγRs) to recruit cellular effector functions. In vitro studies showed that targeting of FcαRI (CD89) by bispecific antibodies (bsAbs) or recombinant IgA resulted in more effective elimination of tumour cells by myeloid effector cells than targeting of FcγR. Here we studied the in vivo anti-tumour activity of IgA EGFR antibodies generated using the variable sequences of the chimeric EGFR antibody cetuximab. Using FcαRI transgenic mice, we demonstrated significant in vivo anti-tumour activity of IgA2 EGFR against A431 cells in peritoneal and lung xenograft models, as well as against B16F10-EGFR cells in a lung metastasis model in immunocompetent mice. IgA2 EGFR was more effective than cetuximab in a short-term syngeneic peritoneal model using EGFR-transfected Ba/F3 target cells. The in vivo cytotoxic activity of IgA2 EGFR was mediated by macrophages and was significantly decreased in the absence of FcαRI. These results support the potential of targeting FcαRI for effective antibody therapy of cancer. © 2013 The Authors.


Raaz-Schrauder D.,University Hospital | Ekici A.B.,University Hospital | Munoz L.E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Klinghammer L.,University Hospital | And 8 more authors.
Autoimmunity | Year: 2012

Patients with Systemic Lupus Erythematosus (SLE) carry an increased risk for the development of coronary artery disease (CAD). The R131 allele of the Fc gamma receptor IIa (FcγRIIa) is associated with SLE incidence and disease severity but also with CAD. Compared to stable angina pectoris (SAP) the unstable angina (UAP), as a manifestation of destabilizing CAD, is associated with increased risk of persistent instability, myocardial infarction, and death. Identification of clinically relevant determinants for unstable angina promises reduction of UAP-associated mortality in patients with SLE. We conducted a clinical study among 553 consecutive patients with stable angina pectoris (n 330) and unstable angina pectoris (n 223). All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa. UAP, but not SAP was significantly associated with the R/R131 genotype (P < 0.001). In troponin-negative patients with angina carrying the R/R131 genotype the odds ratio for suffering from UAP was 4.02 (95% confidence interval, 2.526.41) compared to those with non-R/R131 genotypes. In a multivariable analysis, the R/R131 genotype independently predicted the risk for development of UAP in a model adjusted for classical atherogenic risk factors. Our data imply that risk stratification of SLE- and other high risk patients with troponin-negative angina could be significantly improved by FcγRIIa genotyping. © Informa UK, Ltd.


Otten M.A.,Immunotherapy Laboratory | Bakema J.E.,VUMC | Tuk C.W.,VUMC | Glennie M.J.,Southampton General Hospital | And 5 more authors.
European Journal of Immunology | Year: 2012

Neutrophils potently kill tumour cells in the presence of anti-tumour antibodies in vitro. However, for in vivo targeting, the neutrophils need to extravasate from the circulation by passing through endothelial barriers. To study neutrophil migration in the presence of endothelial cells in vitro, we established a three-dimensional collagen culture in which SK-BR-3 tumour colonies were grown in the presence or absence of an endothelial barrier. We demonstrated that - in contrast to targeting FcγR on neutrophils with mAbs - targeting the immunoglobulin A Fc receptor (FcαRI) instead triggered neutrophil migration and degranulation leading to tumour destruction, which coincided with release of the pro-inflammatory cytokines interleukin (IL)-1β and tumour necrosis factor (TNF)-α. Interestingly, neutrophil migration was enhanced in the presence of endothelial cells, which coincided with production of significant levels of the neutrophil chemokine IL-8. This supports the idea that stimulation of neutrophil FcαRI, but not FcγR, initiates cross-talk between neutrophils and endothelial cells, leading to enhanced neutrophil migration towards tumour colonies and subsequent tumour killing. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Orengo A.M.,Instituto Nazionale per la Ricerca sul Cancro | Fabbi M.,Instituto Nazionale per la Ricerca sul Cancro | Miglietta L.,Instituto Nazionale per la Ricerca sul Cancro | Andreani C.,Instituto Nazionale per la Ricerca sul Cancro | And 13 more authors.
International Journal of Cancer | Year: 2011

Interleukin (IL)-18 is a proinflammatory and immune-enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL-18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro-IL-18) in vitro. In addition, IL-18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL-18 is increased in EOC patients' sera at diagnosis as compared with age-matched healthy women. IL-18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL-18 expression in cytokeratine-positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL-18. The detection of human IL-18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL-18 is tumor-derived. However, IL-18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL-18 present in the ascitic fluid as pro-IL-18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL-18 levels. Altogether these data indicate that IL-18 in EOC fluids is predominantly tumor-derived and that its lack of biological activity may represent a mechanism of tumor-escape. Copyright © 2011 UICC.


Leusen J.H.W.,Immunotherapy Laboratory
Molecular Immunology | Year: 2015

This review is focused on the promises of IgA as a new therapeutic antibody. For more than 30 years IgG molecules have been used in the clinic in the fields of oncology, hematology, auto immune diseases and infections. However, IgA might be a good alternative, since it recruits different effector cells, i.e. polymorphonuclear cells or neutrophils, but can also activate monocytes and macrophages. The present knowledge, but also future direction for IgA- based drugs are discussed. © 2015 Elsevier Ltd.


Brandsma A.M.,Immunotherapy Laboratory | Jacobino S.R.,Immunotherapy Laboratory | Meyer S.,Immunotherapy Laboratory | ten Broeke T.,Immunotherapy Laboratory | Leusen J.H.W.,Immunotherapy Laboratory
Immunological Reviews | Year: 2015

Fc receptors (FcR) are expressed on immune cells and bind to the Fc tail of antibodies. This interaction is essential for FcR-mediated signaling and triggering of cellular effector functions. FcR activation is tightly regulated to prevent immune responses by non-antigen bound antibodies or in the absence of 'danger signals'. FcR activity may be modulated at the plasma membrane via cross-talk with integrins. In addition, cytokines at the site of infection/inflammation can increase FcR avidity, a process referred to as inside-out signaling. This regulatory mechanism has been described for FcγRI (CD64), FcγRIIa (CD32a), and FcαRI (CD89) and is also well-known for integrins. Key cellular events during inside-out signaling are (de)phosphorylation, clustering, cytoskeleton rearrangements, and conformational changes. The latter can be studied with antibodies that specifically recognize epitopes exposed by the active (high affinity) or inactive (low affinity) state of the FcR. These antibodies are important tools to investigate the role of FcR activation in disease settings. Research on FcR has gained momentum with the rise of monoclonal antibodies (mAb) entering the clinic for the treatment of cancer and other diseases. The clinical outcome of mAb therapy may be improved by increasing FcR avidity by cytokine stimulation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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