1,093 research outputs found
Dendritic cell homeostasis is maintained by nonhematopoietic and T-cell-produced Flt3-ligand in steady state and during immune responses
No full textLymphoid-tissue dendritic cells (DCs) are short-lived and need to be continuously replenished from bone marrow-derived DC progenitor cells. Fms-related tyrosine kinase 3 is expressed during cellular development from hematopoietic progenitors to lymphoid-tissue DCs. Fms-related tyrosine kinase 3 ligand (Flt3L) is an essential, nonredundant cytokine for DC progenitor to lymphoid tissue DC differentiation and maintenance. However, which cells contribute to Flt3L production and how Flt3L cytokine levels are regulated in steady state and during immune reactions remains to be determined. Here we demonstrate that besides nonhematopoietic cells, WT T cells produce Flt3L and contribute to the generation of both classical DCs (cDCs) and plasmacytoid DCs in Flt3L(-/-) mice. Upon stimulation in vitro, CD4(+) T cells produce more Flt3L than CD8(+) T cells. Moreover, in vivo stimulation of naïve OT-II CD4(+) T cells with OVA leads to increase of pre-cDCs and cDCs in draining lymph nodes of Flt3L(-/-) mice in a partially Flt3L-dependent manner. Thus, Flt3L-mediated lymphoid tissue DC homeostasis is regulated by steady-state T cells as well as by proliferative T cells, fostering local development of lymphoid organ resident DCs
Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c)-/- mice improves engraftment of human hematopoietic cells in humanized mice
No full textTransplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γ(c)(-/-) (NSG) and BALB/c Rag2(-/-)γ(c)(-/-) mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2(-/-)γ(c)(-/-) mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2(-/-)γ(c)(-/-) mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated
Loss-of-function mutation in ZNF74 is associated with a novel primary immunodeficiency and T cell intrinsic BHLHE40 de-repression
Get PDFKRAB zinc finger proteins (KZFP) are a large family of epigenetic repressors with pleiotropic functions. While the KZFP co-factor KAP-1 has been extensively studied, the physiologic function of individual KZFP members is largely unknown. Within a cohort of patients with primary immunodeficiency (PID), we identified two brothers carrying a homozygosity region on chromosome 22q11 with a truncating loss-of-function mutation in ZNF74 combined with a known disease-associated variant in ADA2. As deficiency of ADA2 (DADA2) has a very variable clinical phenotype, incomplete penetrance and is likely influenced by mutations in modifying genes, we tested the possible influence of the truncating loss-of-function mutation in ZNF74 on the observed clinical phenotype. Analyzing published ChIP-exo-seq data of ZNF74 revealed a binding peak close to an enhancer cluster of BHLHE40, a transcription factor which was highly up-regulated in CD4+ T cell subsets from the index patient. Wild type but not mutant ZNF74 bound to the specific BHLHE40 enhancer site and repressed BHLHE40 in vitro underlining that the BHLHE40 up-regulation seen in the index patient is likely caused by the ZNF74 loss-of-function. Furthermore, transcriptomic analysis of CD4+ T cell subsets from the index patient revealed a tissue resident memory (Trm)-like signature of circulating T cells likely activated by the BHLHE40 de-repression. This could be clinically linked to excessive lymphoma-like T cell infiltrations in skin and bone marrow and an altered memory T cell compartment. Thus, we report the first homozygous loss-of-function mutation in a human KZFP contributing to immune-dysregulation
A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production
No full textHumanized mice are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, the existing models cannot support robust adaptive immune responses, especially the generation of class-switched, antigen-specific antibody responses. Here we describe a new mouse strain, in which human interleukin 6 (IL-6) gene encoding the cytokine that is important for B- and T-cell differentiation was knocked into its respective mouse locus. The provision of human IL-6 not only enhanced thymopoiesis and periphery T-cell engraftment, but also significantly increased class switched memory B cells and serum immunoglobulin G (IgG). In addition, immunization with ovalbumin (OVA) induced OVA-specific B cells only in human IL-6 knock-in mice. These OVA-specific antibodies displayed the highest frequency of somatic mutation, further suggesting that human IL-6 is important for efficient B-cell activation and selection. We conclude that human IL-6 knock-in mice represent a novel and improved model for human adaptive immunity without relying on complex surgery to transplant human fetal thymus and liver. These mice can therefore be used to exploit or evaluate immunization regimes that would be unethical or untenable in humans
Cladribine, cytarabine and idarubicin (CLA-Ida) salvage chemotherapy in relapsed acute myeloid leukemia (AML)
No full textBACKGROUND: The prognosis for relapsing AML patients is disappointing and the preferred salvage chemotherapy is unclear. Among other regimens, cladribine, cytarabine, and idarubicin (CLA-Ida) is used.
METHODS: We analyzed relapsing AML patients receiving CLA-Ida chemotherapy between July 2012 and April 2015 at three academic centers in Switzerland.
RESULTS: Thirty-four patients underwent at least one cycle of CLA-Ida chemotherapy, with 6 patients having two cycles. Treatment-related mortality was 5.9% (2/34 patients). Eighteen patients (52.9%) achieved a complete remission (CR2), and 16 (47.1%) received subsequent allogeneic transplantation, with 8 (23.5%) of these patients remaining in complete remission after a median follow-up of 6 months. In contrast, all 16 patients not achieving CR2 died within 12 months after relapse due to progressive disease.
CONCLUSION: Our data suggest a promising rate of complete remission following CLA-Ida salvage treatment in relapsing AML patients enabling a substantial proportion of such patients to proceed to allogeneic transplantation
Synthesis and analysis of physicochemical properties of sulphonated poly(etherether ketone) and zirconium nanoparticles composite membranes
No full textSulfurēta poli(ēterēterketona) un cirkonija hidrogēnfosfāta nanodaļiņu kompozītmembrānu sintēze un to fizikālķīmisko īpašību analīze. Markus M., zinātniskais vadītājs Dr.ķīm. Guntars Vaivars, konsultants Dr. h. ķīm., prof. Andris Zicmanis. Maģistra darbs, 57 lappuses, 94 attēli, 9 tabulas, 51 literatūras avots, 3 pielikumi. Latviešu valodā. Darbā sintezētas modificēta poli(ēterēterketona) membrānas un to kompozītmembrānas ar cirkonija hidrogēnfosfāta daļiņām, ko paredzēts izmantot degšūnās. Īpaša uzmanība veltīta tādas kompozītmateriāla koncentrāciju attiecību atrašanai, kas nodrošina kvalitatīvu membrānu iegūšanu ar uzlabotām īpašībām tālākas izmantošanas iespējām, kā arī pētīta ultraskaņas ietekme uz membrānas struktūru un daļiņu izmēru kompozītmateriālā. Membrānām veikta skenējošās elektronmikroskopijas analīze, rentgenstaru difraktometrijas analīze un šķīduma daļiņu izmēra un izkliedes analīze, lai izvērtētu iegūto kompozītmembrānu kvalitāti.Synthesis and analysis of physicochemical properties of sulphonated poly(etherether ketone) and zirkonium nanoparticles composite membranes. The author Madara Markus, supervisor Dr. Chem. Vaivars G. Consultant Dr. h. chem., prof. Zicmanis A. Master paper, 57 pages, 94 figures, 9 tables, 51 literature references, 3 apposition. In Latvian. Modified poly(etheretherketone) membranes and zirconium nanoparticles composite membranes usable for fuel cells were synthesized. In this paper special attention was devoted to find a composite concentration ratio, which provides high-qualiy membranes acquition with improved characteristics, as well as effect of use of ultrasonic on structure of composite membranes. Analysis of membrane surface with SEM was made, XRD analysis to find out structure of membranes was made and particle size distribution of composite solution was measured, in order to assess the quality of the resulting composite membranes
Financial implications of cancer. Empirical data and ethical aspects
No full textMehlis K, Witte J, Surmann B, et al. Financial implications of cancer. Empirical data and ethical aspects. In: Manz MG, ed. Abstractband für die Virtuelle Jahrestagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Medizinische Onkologie, 09.–11. Oktober 2020: Abstracts. Oncology Research and Treatment . Vol 43. Basel: Karger; 2020: 21-22
In vivo divisional tracking of hematopoietic stem cells
No full textHematopoietic stem cell (HSC) division leads to self-renewal, differentiation, or death of HSCs, and adequate balance of this process results in sustained, lifelong, high-throughput hematopoiesis. Despite their contribution to hematopoietic cell production, the majority of cells within the HSC population are quiescent at any given time. Recent studies have tackled the questions of how often HSCs divide, how divisional history relates to repopulating potential, and how many HSCs contribute to hematopoiesis. Here, we summarize these recent findings on HSC turnover from different experimental systems and discuss hypothetical models for HSC cycling and maintenance in steady-state and upon hematopoietic challenge
Regulation of inflammation- and infection-driven hematopoiesis
No full textInnate myeloid immune cells, and neutrophils in particular, serve as first line of defense against pathogenic microorganisms including bacteria and fungi. Given their short life span during steady-state conditions, myeloid cells - with, in some cases, the exception of tissue macrophages - need to be constantly regenerated from hematopoietic stem and progenitor cells. During severe systemic bacterial infection, myeloid cell turnover is dramatically increased due to their unique modus operandi in combating invading pathogens involving release of lytic enzymes and neutrophil extracellular traps. Consequently, steady-state hematopoiesis is switched to emergency hematopoiesis by launching a unique hematopoietic response program that is aimed at greatly increasing myeloid cell output to meet the higher demand. In this review, we will discuss well-established as well as recently emerging concepts around the regulation of this fundamental process
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