TY - JOUR AU - Mooij, C.E.M. de AU - Netea, M.G. AU - Velden, W.J.F.M. van der AU - Blijlevens, N.M.A. PY - 2017 UR - https://hdl.handle.net/2066/174668 AB - Interleukin-1alpha (IL-1alpha) and IL-1beta are potent inflammatory cytokines that activate local and systemic inflammatory processes and are involved in protective immune responses against infections. However, their dysregulated production and signaling can aggravate tissue damage during infection, inflammatory diseases, and chemotherapy-induced intestinal mucositis. Additionally, cytokines of the IL-1 family play an important role in homeostatic as well as "emergency" hematopoiesis and are involved in the pathogenesis of several myeloid and lymphoid hematological malignancies. In the pathogenesis of intestinal mucositis and graft-versus-host disease (GVHD), these cytokines are considered pivotal during the initiation as well as propagation phase, and insights from animal studies suggest that targeting the IL-1 pathway can significantly ameliorate mucositis and GVHD. Moreover, IL-1alpha and IL-1beta might prove to be valuable targets for both prevention and treatment of cancer and cancer therapy-related complications, and the first clinical studies have already been performed in the setting of hematological malignancies. In this review, we will discuss the role of cytokines of the IL-1 family in hematological malignancies, chemotherapy-induced intestinal mucositis, and GVHD, and speculate on possibilities of therapeutically targeting the IL-1 pathway in hematological patients. TI - Targeting the interleukin-1 pathway in patients with hematological disorders EP - 3164 SN - 0006-4971 IS - iss. 24 SP - 3155 JF - Blood VL - vol. 129 DO - https://doi.org/10.1182/blood-2016-12-754994 ER - TY - JOUR AU - Stevens, W.B.C. AU - Netea, M.G. AU - Kater, A.P. AU - Velden, W.J.F.M. van der PY - 2016 UR - https://hdl.handle.net/2066/172210 AB - In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed 'trained immunity'. In this review the concept of 'trained immunity' is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis. TI - 'Trained immunity': consequences for lymphoid malignancies EP - 1468 SN - 0390-6078 IS - iss. 12 SP - 1460 JF - Haematologica VL - vol. 101 DO - https://doi.org/10.3324/haematol.2016.149252 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/172210/172210.pdf?sequence=1 ER - TY - JOUR AU - Chai, L. AU - Boer, M.G. de AU - Velden, W.J. van der AU - Plantinga, T.S. AU - Spriel, A.B. van AU - Jacobs, C.W. AU - Halkes, C.J. AU - Vonk, A.G. AU - Blijlevens, N.M.A. AU - Dissel, J.T. van AU - Donnelly, P. AU - Kullberg, B.J. AU - Maertens, J. AU - Netea, M.G. PY - 2011 UR - https://hdl.handle.net/2066/98410 AB - BACKGROUND: Dectin-1 is the major receptor for fungal beta-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients. METHODS: Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism. RESULTS: The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%-7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77-4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus. CONCLUSIONS: Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings. TI - The Y238X stop codon polymorphism in the human beta-glucan receptor dectin-1 and susceptibility to invasive aspergillosis EP - 743 SN - 0022-1899 IS - iss. 5 SP - 736 JF - The Journal of Infectious Diseases VL - vol. 203 DO - https://doi.org/10.1093/infdis/jiq102 ER - TY - JOUR AU - Velden, W.J.F.M. van der AU - Plantinga, T.S. AU - Donnelly, J.P. AU - Kullberg, B.J. AU - Blijlevens, N.M.A. AU - Netea, M.G. PY - 2010 UR - https://hdl.handle.net/2066/88317 AB - Host-pathogen interactions at epithelial barriers play an important role in health and disease. This also applies to the clinical setting of stem cell transplantation (SCT) in which deregulated sensing of microbes and their cell wall components by pattern recognition receptors (PRRs) can contribute to inflammatory and infectious complications. The role of Candida species herein has recently been rediscovered since a 'loss-of-function' Y238X polymorphism in dectin-1, a C-type lectin receptor recognizing the beta-1,3-glucan motif of Candida, resulted in diminished membrane expression and lower cytokine responses upon beta-1,3-glucan recognition, and was associated with increased Candida colonization of SCT recipients, rendering them at risk for candidaemia. In addition, Candida colonization was associated with an increased incidence of acute graft-versus-host disease (GvHD), but only in those individuals with the wild-type dectin-1 allele. The Th17 mediated immune responses might provide a common link in these processes, as they have recently been implicated in anti-Candida immunity as well as the pathogenesis of GvHD. These new insights suggest that immunogenetics could contribute to a more individualized risk-based strategy for managing SCT recipients, for example concerning antifungal prophylaxis. In addition, modulating host-pathogen interactions by selectively modulating PRR activity could be exploited in SCT to achieve better outcomes. TI - Host-microbe interactions in stem cell transplantation: recognizing Candida in infection and inflammation. EP - 184 SN - 2150-5594 IS - iss. 3 SP - 180 JF - Virulence VL - vol. 1 DO - http://dx.doi.org/10.4161/viru.1.3.11208 ER - TY - JOUR AU - Velden, W.J.F.M. van der AU - Plantinga, T.S. AU - Feuth, T. AU - Donnelly, J.P. AU - Netea, M.G. AU - Blijlevens, N.M.A. PY - 2010 UR - https://hdl.handle.net/2066/87797 AB - Dectin-1 plays an important role in antifungal immunity. The dectin-1 Y238X polymorphism, which results in decreased Th17 responses, is associated with increased Candida colonization of stem cell transplantation (SCT) recipients. In this study we found no impact of the polymorphism on the incidence of graft-versus-host disease (GvHD), or on disease-free and overall survival in these SCT recipients. However, patients from patient-donor pairs bearing the wild-type allele who where colonized with Candida had a significant increased incidence of acute GvHD compared to non-colonized patients (OR=2.6, P=0.04). The fact that this was not the case in patients from pairs with the Y238X polymorphism (OR=1.2, ns) suggests that despite increased colonization defective dectin-1 signaling might have prevented an impact of Candida colonization on the incidence of acute GvHD to occur. These are the first human data showing a role for Candida in the pathogenesis of acute GvHD. The mechanism could involve C-type lectin receptor mediated Th17 responses. TI - The incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status. EP - 306 SN - 1521-6616 IS - iss. 2 SP - 302 JF - Clinical Immunology VL - vol. 136 N1 - 1 augustus 2010 DO - http://dx.doi.org/10.1016/j.clim.2010.04.007 ER -