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1.
Vox Sang ; 2024 Jun 23.
Article in English | MEDLINE | ID: mdl-38922929

ABSTRACT

Autoimmune haemolytic anaemia (AIHA) is characterized by an increased destruction of red blood cells due to immune dysfunction and auto-antibody production. Clinical manifestations are mainly related to anaemia, which can become life-threatening in case of acute haemolysis. Aiming at counterbalancing severe anaemia, supportive treatments for these patients frequently include transfusions. Unfortunately, free serum auto-antibodies greatly interfere in pre-transfusion testing, and the identification of compatible red blood cell units for AIHA patients can be challenging or even impossible. Problems faced in pre-transfusion testing often lead to delay or abandonment of transfusions for AIHA patients. In this review, we discuss publications concerning global transfusion management in AIHA, with a focus on pre-transfusion testing, and practical clues to manage the selection of transfusion units for these patients. Depending on the degree of transfusion emergency, we propose an algorithm for the selection and laboratory testing of units to be transfused to AIHA patients.

2.
Ther Adv Hematol ; 14: 20406207231199837, 2023.
Article in English | MEDLINE | ID: mdl-37780945

ABSTRACT

Background: For more than 2 years medical practice has been dealing with the Covid-19 pandemic. Atypical symptoms, such as frostbites and acrosyndromes, have appeared, and autoimmune anemias (some of which with cold agglutinins) have been described. Objectives: We planned to study the prevalence of positive direct Coombs tests (DCTs) and hemolytic autoimmune anemia in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its correlation with complications, and then investigate the impact of the infection on iron metabolism. Design: This is an observational, cross-sectional, single-center, exploratory study. Methods: We obtained Coombs tests in a population of 179 infected patients at the CHU of Liège. We then studied iron metabolism in some of these patients, by measuring serum ferritin, erythropoietin (EPO), erythroferrone and hepcidin. Results: We did not identify any case of autoimmune hemolysis. However, there was a 20.3% prevalence of positive DCT, mainly with IgG (91.7%). These patients, compared to DCT-negative patients, were not only more anemic and transfused, but also required more transfers to intensive care units and had longer hospital stays and mechanical ventilation. The pattern of anemia was consistent with the anemia of inflammation, showing elevated hepcidin and ferritin levels, while EPO and erythroferrone values were lower than expected at this degree of anemia. Erythroferrone was higher and Hb was lower in DCT-positive patients. Finally, we identified a correlation between iron parameters and complicated forms of infection. Conclusion: Covid-19 patients suffered from inflammatory anemia with more severe forms of infection correlated to positive DCT status. This could potentially be of interest for future clinical practice.

3.
PLoS One ; 11(12): e0167997, 2016.
Article in English | MEDLINE | ID: mdl-27942010

ABSTRACT

BACKGROUND: Sclerodermatous chronic Graft-versus-Host Disease (scl-cGVHD) is one of the most severe form of cGVHD. The Platelet-derived Grotwth Factor (PDGF) and the Transforming Growth Factor-ß (TGF-ß) play a significant role in the fibrosing process occurring in scl-cGVHD. This prompted us to assess the impact of the PDGF-r and c-Abl tyrosine kinase inhibitor imatinib on scl-cGVHD. METHODS: To assess the impact of imatinib on T cell subset proliferation in vivo, Balb/cJ recipient mice were lethally (7 Gy) irradiated and then injected with 10x106 bone marrow cells from B10.D2 mice on day 0. Fourteen days later, 70x106 carboxyfluorescein succinimidyl ester (CFSE)-labeled splenocytes from B10.D2 mice were infused and imatinib or sterile water was administered for 5 days. To induce severe scl-cGVHD, Balb/cJ mice were injected i.v. with 10.106 bone marrow cells and 70.106 splenocytes from B10.D2 donor mice after 7 Gy irradiation. Mice were then given sterile water or imatinib from day +7 after transplantation to the end of the experiment (day +52). RESULTS: Imatinib decreased the proliferation of total T cells (P = 0.02), CD8+ T cells (P = 0.01), and of regulatory T cells (Tregs) (P = 0.02) in the spleen. In the severe scl-cGVHD model, imatinib-treated mice had significantly lower levels of PDGF-r phosphorylation than control mice on day 29 after transplantation (P = 0.008). However, scl-cGVHD scores were similar between vehicle- and imatinib-treated mice during the whole experiment, while there was a suggestion for less weight loss in imatinib-treated mice that reached statistical significance at day +52 following transplantation (P = 0.02). CONCLUSIONS: Imatinib had a limited impact in murine scl-cGVHD despite significant inhibition of PDGF-r.


Subject(s)
Graft vs Host Disease/drug therapy , Imatinib Mesylate/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Scleroderma, Localized/drug therapy , T-Lymphocytes/drug effects , Animals , Cell Proliferation/drug effects , Disease Models, Animal , Graft vs Host Disease/immunology , Graft vs Host Disease/physiopathology , Mice , Mice, Inbred BALB C , Platelet-Derived Growth Factor/metabolism , Proto-Oncogene Proteins c-abl/metabolism , Scleroderma, Localized/immunology , Scleroderma, Localized/physiopathology , T-Lymphocyte Subsets/drug effects , T-Lymphocytes/immunology
4.
Cell Mol Life Sci ; 73(24): 4611-4622, 2016 12.
Article in English | MEDLINE | ID: mdl-27491297

ABSTRACT

An increase in autoimmune diseases poses a socioeconomic challenge worldwide. Predisposing genetic risk has been identified, yet environmental factors make up a significant part of the risk in disease initiation and propagation. Next to improved hygiene and a gross reduction of infections, changes in dietary habits are one of the most evident Western lifestyle factors potentially associated with the increase in autoimmune diseases. Growing evidence suggests that particularly a typical 'Western diet', rich in saturated fat and salt and related pathologies can have a profound impact on local and systemic immune responses under physiologic and autoimmune conditions such as in multiple sclerosis (MS). In this review, we discuss recent findings on environmental factors influencing autoimmunity with an emphasis on the impact of 'Western diet' on immune homeostasis and gut microbiota in MS.


Subject(s)
Environment , Multiple Sclerosis/etiology , Animals , Fatty Acids/adverse effects , Humans , Lymphocytes/immunology , Multiple Sclerosis/immunology , Risk Factors
5.
Oncotarget ; 7(25): 37931-37943, 2016 Jun 21.
Article in English | MEDLINE | ID: mdl-27177328

ABSTRACT

Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of tumor cells in the bone marrow (BM) and is associated with immunosuppression, angiogenesis and osteolysis. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature, immunosuppressive myeloid cells that promote tumor progression through different mechanisms.In this work, we studied the contribution of MDSC subsets to different disease-promoting aspects in MM. We observed an expansion of polymorphonuclear/granulocytic (PMN-)MDSCs in two immunocompetent murine MM models, while this was not observed for monocytic (MO-)MDSCs. Both MDSC subpopulations from MM-bearing mice were immunosuppressive, but PMN-MDSCs displayed a higher suppressive potential. Soluble factors secreted by MM cells increased the viability of MDSCs, whereas the presence of MDSCs did not affect the proliferation of MM cells in vitro or in vivo. Interestingly, we observed a pro-angiogenic effect of PMN-MDSCs in the context of MM using the chick chorioallantoic membrane assay. Consistently, MM-derived PMN-MDSCs showed an up-regulation of angiogenesis-related factors and reduced PMN-MDSC levels were associated with less angiogenesis in vivo. Finally, we identified MO-MDSCs as osteoclast precursors.These results suggest that MDSC subpopulations play diverging roles in MM. We show for the first time that PMN-MDSCs exert a pro-angiogenic role in MM.


Subject(s)
Granulocytes/metabolism , Multiple Myeloma/genetics , Myeloid-Derived Suppressor Cells/metabolism , Neovascularization, Pathologic/metabolism , Animals , Humans , Mice , Multiple Myeloma/pathology , Neovascularization, Pathologic/pathology
6.
Oncotarget ; 7(21): 30712-29, 2016 May 24.
Article in English | MEDLINE | ID: mdl-27095574

ABSTRACT

Multiple myeloma (MM)-associated osteolytic bone disease is a major cause of morbidity and mortality in MM patients and the development of new therapeutic strategies is of great interest. The proto-oncogene SRC is an attractive target for such a strategy. In the current study, we investigated the effect of treatment with the SRC inhibitor saracatinib (AZD0530) on osteoclast and osteoblast differentiation and function, and on the development of MM and its associated bone disease in the 5TGM.1 and 5T2MM murine MM models. In vitro data showed an inhibitory effect of saracatinib on osteoclast differentiation, polarization and resorptive function. In osteoblasts, collagen deposition and matrix mineralization were affected by saracatinib. MM cell proliferation and tumor burden remained unaltered following saracatinib treatment and we could not detect any synergistic effects with drugs that are part of standard care in MM. We observed a marked reduction of bone loss after treatment of MM-bearing mice with saracatinib as reflected by a restoration of trabecular bone parameters to levels observed in naive control mice. Histomorphometric analyses support that this occurs through an inhibition of bone resorption. In conclusion, these data further establish SRC inhibition as a promising therapeutic approach for the treatment of MM-associated osteolytic bone disease.


Subject(s)
Benzodioxoles/therapeutic use , Multiple Myeloma/drug therapy , Osteolysis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogenes/drug effects , Quinazolines/therapeutic use , src-Family Kinases/antagonists & inhibitors , Administration, Oral , Animals , Bone and Bones/drug effects , Bone and Bones/pathology , Cell Differentiation/drug effects , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Inbred C57BL , Multiple Myeloma/complications , Multiple Myeloma/pathology , Osteoblasts/drug effects , Osteoclasts/drug effects , Osteolysis/etiology , Osteolysis/pathology , Proto-Oncogene Mas
7.
Cancer Immunol Immunother ; 64(8): 989-98, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25971542

ABSTRACT

Multiple myeloma (MM) is characterized by the accumulation of monoclonal plasma cells in the bone marrow and causes several immune alterations in patients. Thymosin α1 (Tα1) is a thymic peptide that has been associated with immuno-stimulating properties. In addition, this peptide exerts anti-tumor effects in several cancer types. Beneficial effects of Tα1 administration have also been shown on immune reconstitution after hematopoietic stem cell transplantation (HSCT), a current treatment modality in hematological malignancies including MM. In this study, we observed a slight reduction in the proliferation of murine and human MM cell lines in the presence of Tα1 in vitro. However, using two immunocompetent murine MM models (5TGM1 and MOPC315.BM), we did not observe any impact of Tα1 administration on MM development in vivo. Furthermore, no beneficial effects of Tα1 treatment were observed on lymphocyte immune reconstitution after transfusion of human hematopoietic stem cells into immunodeficient mice. In conclusion, despite direct effects of Tα1 on human MM cell line proliferation in vitro, Tα1 did not exert anti-myeloma effects in vivo in the two murine models tested. Moreover, Tα1 failed to improve immune recovery in a xenogeneic HSCT model.


Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Peptide Fragments/administration & dosage , Thymosin/analogs & derivatives , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Immunomodulation/drug effects , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, SCID , Multiple Myeloma/immunology , Peptide Fragments/adverse effects , Thymalfasin , Thymosin/administration & dosage , Thymosin/adverse effects , Xenograft Model Antitumor Assays
8.
Biomed Res Int ; 2015: 718539, 2015.
Article in English | MEDLINE | ID: mdl-25664323

ABSTRACT

Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021.


Subject(s)
Agaricus/chemistry , Hematopoietic Stem Cell Transplantation , Immunologic Factors/therapeutic use , Multiple Myeloma/drug therapy , Tissue Extracts/therapeutic use , Adult , Aged , Animals , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Membrane/metabolism , Cell Proliferation/drug effects , Chemokines/metabolism , Complex Mixtures , Dose-Response Relationship, Drug , Double-Blind Method , Female , Gene Expression Regulation , Humans , Immunologic Factors/pharmacology , Intercellular Signaling Peptides and Proteins/metabolism , Leukapheresis , Male , Mice , Middle Aged , Multiple Myeloma/genetics , Signal Transduction/genetics , Survival Analysis , Time Factors , Tissue Extracts/pharmacology , Transplantation, Autologous , Treatment Outcome
9.
PLoS One ; 9(11): e113764, 2014.
Article in English | MEDLINE | ID: mdl-25415267

ABSTRACT

BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD). METHODS AND RESULTS: Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vß spectratyping analysis identified Vß families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vß families within CD4 T cells were associated exclusively with either GvM or GvHD responses. CONCLUSIONS: We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vß spectratyping, we also demonstrated the presence of GvM unique responses potentially associated with the curative capacity of this immunotherapeutic approach.


Subject(s)
Graft vs Tumor Effect/immunology , Hematopoietic Stem Cell Transplantation , Multiple Myeloma/therapy , Neoplasms, Experimental/therapy , Allografts , Animals , Female , Male , Mice , Mice, Inbred BALB C , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology
10.
PLoS One ; 8(5): e62818, 2013.
Article in English | MEDLINE | ID: mdl-23667526

ABSTRACT

Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.


Subject(s)
Angiogenesis Inducing Agents/metabolism , Angiogenesis Inhibitors/pharmacology , Multiple Myeloma/pathology , Plicamycin/pharmacology , Up-Regulation/drug effects , Animals , Aorta/drug effects , Aorta/metabolism , Aorta/physiology , Bone Marrow Cells/cytology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Endothelial Cells/drug effects , Humans , Mice , Neovascularization, Physiologic/drug effects , Rats , Xenograft Model Antitumor Assays
11.
Int J Hematol ; 94(6): 505-18, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22086206

ABSTRACT

Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant expansion of malignant plasma cells within the bone marrow (BM). One of the hallmarks of this disease is the close interaction between myeloma cells and neighboring cells within the BM. Angiogenesis, through the activation of endothelial cells, plays an essential role in MM biology. In the current review, we describe the angiogenesis process in MM by identifying the interacting cells, the pro- and anti-angiogenic cytokines modulated, and the extracellular matrix degrading proteases liable to participate in the pathophysiology. Finally, we highlight the impact of hypoxia (through hypoxia-inducible factor-1) and constitutive activation of nuclear factor-κB in this tumor-induced neo-vascularization.


Subject(s)
Multiple Myeloma/blood supply , Neovascularization, Pathologic/metabolism , Antineoplastic Agents/therapeutic use , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Stromal Cells/metabolism
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