243 research outputs found
A possible role for CCL27/CTACK-CCR10 interaction in recruiting CD4+ T cells to skin in human graft-versus-host disease
No full textGraft-versus-host disease (GvHD) is a serious complication of allogeneic stem cell transplantation (SCT) affecting the skin, gut and liver. The involvement of distinct organs suggests a role for tissue-specific chemokines and their receptors in directing activated donor T cells to these sites. In this study the potential involvement of the skin-specific CCL27/CTACK-CCR10 interaction was investigated in 15 paediatric SCT patients with skin GvHD. During the course of skin GvHD, peripheral blood T cells from these patients contained a high proportion of CD4+ CCR10+ T cells that disappeared after the GvHD was resolved. These cells were CD45RO+, expressed additional skin homing markers (cutaneous lymphocyte-associated antigen and CCR4), and produced the T-cell helper type 1-cytokines tumour necrosis factor-alpha and interleukin-2. The increase in CD4+ CCR10+ T cells was absent in SCT patients without GvHD. Immunohistochemical investigations showed CD4+ CCR10+ T cells in the GvHD skin biopsies of the same patients, but not in the gut biopsies of patients also suffering from gut GvHD. The infiltration of CD4+ CCR10+ T cells in the GvHD-affected skin correlated with an enhanced epidermal expression of CCL27/CTACK, the ligand for CCR10. These findings support the involvement of CCL27/CTACK-CCR10 interaction in recruiting CD4+ T cells to the skin, thus contributing to the pathogenesis of acute GvHD.Faaij, Claudia M. J. M. ; Lankester, Arjan C. ; Spierings, Eric ; Hoogeboom, Manja ; Bowman, Edward P. ; Bierings, Marc ; Révész, Tom ; Egeler, R. Maarten ; Van Tol, Maarten J. D. ; Annels, Nicola
Faculty Opinions recommendation of Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients.
No full textCorrection: Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?—A multicenter EBMT-PDWP study (Bone Marrow Transplantation, (2020), 55, 8, (1540-1551), 10.1038/s41409-020-0854-0)
No full textThe article “Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?—A multicenter EBMT-PDWP study,” written by Andre Manfred Willasch, Christina Peters, Petr Sedláček, Jean-Hugues Dalle, Vassiliki Kitra-Roussou, Akif Yesilipek, Jacek Wachowiak, Arjan Lankester, Arcangelo Prete, Amir Ali Hamidieh, Marianne Ifversen, Jochen Buechner, Gergely Kriván, Rose-Marie Hamladji, Cristina Diaz-de-Heredia, Elena Skorobogatova, Gérard Michel, Franco Locatelli, Alice Bertaina, Paul Veys, Sophie Dupont, Reuven Or, Tayfun Güngör, Olga Aleinikova, Sabina Sufliarska, Mikael Sundin, Jelena Rascon, Ain Kaare, Damir Nemet, Franca Fagioli, Thomas Erich Klingebiel, Jan Styczynski, Marc Bierings, Kálmán Nagy, Manuel Abecasis, Boris Afanasyev, Marc Ansari, Kim Vettenranta, Amal Alseraihy, Alicja Chybicka, Stephen Robinson, Yves Bertrand, Alphan Kupesiz, Ardeshir Ghavamzadeh, Antonio Campos, Herbert Pichler, Arnaud Dalissier, Myriam Labopin, Selim Corbacioglu, Adriana Balduzzi, Jacques-Emmanuel Galimard, Peter Bader, on behalf of the EBMT Paediatric Diseases Working Party, was originally published online first without Open Access. After publication in volume 55, issue 8, page 1540–1551, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 InternationalS License, which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third-party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/ 4.0. Open access funding was enabled and organized by Projekt DEAL
Adenoviral Infections in the immunocompromised host towards tailor-made therapy
No full textAdenoviruses (HAdV) can cause serious life threatening infections, especially in pediatric patients after allogeneic stem cell transplantation (SCT). To improve the morbidity and mortality rate of HAdV infected patients after SCT three issues have been explored: which patients are at risk for HAdV infection, what is the best treatment for HAdV infected patients and when do we start treatment. We found that in pediatric patients HAdV-DNA positivity in nasopharyngeal aspirate before SCT is a very important risk factor for developing invasive HAdV infection after SCT. As determined with multiplex immuno-assay we also found that children with a localized HAdV infection have a different cytokine profile compared with patients with an invasive HAdV infection after SCT. Cytokine signatures can also be helpful to differentiate invasive HAdV infection from other SCT related complications as Graft versus Host Disease (GvHD) and Epstein-barr virus infection. Immune profiling could possibly help to identify patients at high risk in an earlier stage. Because no effective medication for HAdV infection exists and HAdV-specific T-cells are critically involved in virus elimination, an alternative treatment option is the adoptive transfer of HAdV-specific T-cells from the graft donor into the recipient. One of the potential risks of using HAdV-specific T-cells for adoptive therapy is the risk for GvHD. The use of a high purity of HAdV-specific CD4+ T-cells would strongly reduce this risk. By using a computer algorithm designed to predict pan HLA-DR binding T-cell epitopes we detected six 15-mer epitopes from HAdV. These epitopes induce a proliferative T-cell response in the majority of healthy controls. By culturing peripheral blood mononuclear cells (PBMCs) of healthy donors with identified HAdV epitopes it is possible to generate CD4+ HAdV-specific T-cells. With artificial antigen presenting cells, composed of liposomes harboring a HAdV-peptide and MHC-class II complex, these HAdV-specific T-cells could be isolated. Isolated HAdV CD4+ specific T-cells are fully functional, produce pro-inflammatory cytokines, express the cytotoxins perforin and granzyme B, kill HAdV-infected cells effectively and do not show alloreactivity. Because umbilical cord blood transplants (UCB) emerge as an alternative stem cell source for SCT, and immune reconstitution is delayed in patients receiving UCB, higher infection rates with HAdV are expected to emerge. In case of HAdV infection after UCB transplantation adoptive therapy with HAdV-specific T-cells derived from cord blood seems also a promising treatment option. However, the induction of HAdV-specific T-cells from UCB requires the priming and expansion of naive T-cells rather than expansion of pre-existing virus-specific memory T-cells. By stimulating cord blood mononuclear cells with 15-mer peptides we showed that HAdV-specific T-cells could be generated. The HAdV-specific T-cells produce pro-inflammatory cytokines, perforin and granzyme B, all necessary for viral elimination. The generation of HAdV-specific T-cells in response to HAdV peptides seems an essential step in developing tailor-made therapy for HAdV infection for recipients of SCT transplants. In the near future probably high-risk patients may be treated prophylactically with adoptive transfer of HAdV-specific T-cells, possibly in association with antiviral medication. These new approaches hopefully will lead to reduction in incidence and mortality rate associated with HAdV infection after SCT
How I manage children with Diamond-Blackfan anaemia
No full textDiamond-Blackfan anaemia (DBA) is a rare inherited marrow failure disorder, characterized by hypoplastic anaemia, congenital anomalies and a predisposition to cancer as a result of ribosomal dysfunction. Historically, treatment is based on glucocorticoids and/or blood transfusions, which is accompanied by significant toxicity and long-term sequelae. Currently, stem cell transplantation is the only curative option for the haematological DBA phenotype. Whereas this procedure has been quite successful in the last decade in selected patients, novel therapies and biological insights are still warranted to improve clinical care for all DBA patients. In addition to paediatric haematologists, other physicians (e.g. endocrinologist, gynaecologist) should ideally be involved in the care of this chronic condition from an early age, to improve lifelong management of haematological and non-haematological symptoms, and screen for DBA-associated malignancies. Here we provide an overview of current knowledge and recommendations for the day-to-day care of DBA patients
Placental iron uptake and its regulation
No full textIron transport in pregnancy is an active one-way process, from mother
to fetus.
Early in gestation fetal iron needs are low, and so is trans-placental
transport, but as erythropoiesis develops, rising fetal iron needs are
met by trans-placental iron transport.
Apparently, the fetus is protected against iron toxicity as well as
against iron deficiency, the latter even if maternal iron stores are
depleted.
Fetectomy experiments in animals indicate that placental iron uptake
is an autonomous process, independent of the presence of a fetus.
The narrow and, in the course of pregnancy, enonnously changing difference
between iron deficiency and iron toxicity strongly suggests that
maternal-fetal iron transport needs to be regulated.
This thesis deals with some aspects of the regulation of placental
iron uptake. Cllapter 3 describes the development of a cell culture
model to study placental iron uptake. Cllapter 4 deals with characteristics
of transferrin receptors in these cells and chapter 5 describes
the regulation of transferrin receptor expression in nonnal hmnan
term trophoblast cells in vitro.
Finally, chapter 6 describes pregnancy-related changes of maternal
transferrin, the iron donor for the placenta.
In this chapter an animal model is used, the guinea-pig
Steering myelopoiesis: a role for protein acetylation?
No full textEpigenetic changes have been identified as important factors in the pathogenesis of haematological malignancies, which has resulted in a rapid increase in the use of chromatin modulating drugs, including lysine deacetylase inhibitors (KDACi, or histone deacetylase (HDAC) inhibitors). While the effects of KDACi on histone acetylation resulting in chromatin remodelling and subsequent activation of the transcriptional machinery have been studied extensively, the regulation of acetylation of non-histone proteins, in the context of disease, is not well understood. Since KDACi have proven to be very effective in myeloid disorders, including myelodysplastic syndrome (MDS), and acute myeloid leukemie (AML), this suggests that the regulation of protein acetylation plays an important role in aberrant myeloid differentiation, and raises questions as to the role of protein acetylation in normal myelopoiesis. It is therefore important to define the effects of this family of compounds on the normal hematopoietic compartment. In this thesis we sought to investigate the effects of KDACi in normal hematopoiesis, focusing on myeloid development towards the granulocyte/macrophage lineage, and megakaryocyte/erythroid lineage in order to increase our understanding of the effects of KDACi in myeloid disorders, regulation of their well-described molecular targets, and to identify novel protein substrates functionally regulated by acetylation during myeloid development. We report several novel findings including: i) KDAC inhibition regulates cell fate decisions during neutrophil development, which are distinct from the effects in malignant cells, (ii) the commonly used KDACi valproic acid (VPA) alters the proportion of leukocyte subsets in non-hematological patient groups, (iii) functional activity of the granulocyte-specific transcription factor C/EBPε is regulated by acetylation, and deacetylation, (iv) modulation of protein acetylation by class I/II KDAC, or class III KDAC/ SIRTi, differentially modulates megakaryocyte and erythroid development. In addition we report the effects of nitrostyrene derivatives, compounds most frequently studied as anti-cancer drugs, on the expansion and differentiation of myeloid progenitors, involving regulation of p38MAPK and C/EBPα activity, key regulators of myeloid development. Taken together, the knowledge concerning the role of epigenetic aberrancies in the pathogenesis of (myeloid) malignancies is increasing, resulting in a rapidly expanding research field focusing on the development of novel, targeted therapies. We have demonstrated that, in order to clinically use KDACi, and other epigenetic drugs, it is extremely important to define the effects of these compounds on normal hematopoiesis
Immunity and infectious morbidity in childhood ALL treatment : the benefits of intensity reduction
No full textWith current childhood acute lymphoblastic leukemia (ALL) treatment protocols the cure rate approaches 90%. In the 10 percent of case fatalities, 2 major challenges stand out: incurable relapses of ALL and (infectious) deaths-in-remission. Thus, reducing toxicity is becoming an important goal to further improve childhood ALL survival. The Dutch Childhood Oncology Group (DCOG) ALL 10 protocol was designed to investigate whether a reduction of chemotherapeutic treatment intensity after a standard initial treatment phase is possible for patients with a good prognosis (standard risk; SR), based on minimal residual disease measurement, and whether further intensification of therapy improves the outcome for medium risk (MR) and high risk patients. We prospectively compared infectious complications and damage to the immune system during and following SR reduced versus conventional MR treatment. 171 patients (SR, 54; MR, 117) were included in the study on infectious morbidity. All parents of patients kept a daily log in which all episodes of fever were reported, which were systematically reviewed in the clinical files. SR reduced intensification/maintenance chemotherapy resulted in significantly less infectious morbidity compared with MR treatment. SR patients had significantly fewer febrile episodes and hospitalizations for fever compared with MR patients. In addition, infections of SR patients were less severe. Hospitalizations for fever were clustered mainly in the identical induction/HD-MTX phase, the first half of the MR intensification/maintenance phase but also the second half of the MR intensification/maintenance phase showed significantly more hospitalizations compared with the SR group. In a subgroup of patients, B and T cell subpopulations were analyzed during and after chemotherapy. Regarding lymphocyte subpopulations, transitional and naive B cells were more affected than memory B cell subpopulations, especially in the MR group. The IgG+/A+, IgM+ and IgM only memory B cells were significantly reduced during chemotherapy; significantly less in the SR group. One year after chemotherapy cessation, increased B cell numbers were found, consisting mainly of transitional and naive B cells while CD27+IgG+/A+, IgM+ and IgM only memory B cells had still not fully recovered. The T cell compartment was less but also significantly affected during chemotherapy. CD4+ T cells were most affected compared with CD8+ T cells although both recovered to normal ranges within 1 year after chemotherapy cessation. Immunoglobulin levels showed significantly different patterns between the SR and MR groups. In the MR group IgG, IgA and IgM levels decreased towards the end of treatment; in the SR group IgG levels increased during intensification/maintenance phase, while IgA and IgM stabilized. In both groups IgM and IgG levels were most affected. Specific antibody levels against diphteria, tetanus and B. pertussis all continued to decline in both groups. Still, SR treatment resulted in higher specific antibody levels than MR treatment. In conclusion, levels of T and B cell subpopulations together with immunoglobulin and specific antibody concentrations were less affected by reduced intensity chemotherapy which was, next to less frequent episodes of neutropenia, reflected in a major reduction in infectious morbidity. The beneficial effect of treatment reduction on specific antibody levels seemed only margina
HLA-identical umbilical cord blood transplantation from a sibling donor in juvenile myelomonocytic leukemia.
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