Publications by authors named "Andrzej Eljaszewicz"

37 Publications

Chronic Diabetic Wounds and Their Treatment with Skin Substitutes.

Cells 2021 Mar 15;10(3). Epub 2021 Mar 15.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland.

With the global prevalence of type 2 diabetes mellitus steeply rising, instances of chronic, hard-healing, or non-healing diabetic wounds and ulcers are predicted to increase. The growing understanding of healing and regenerative mechanisms has elucidated critical regulators of this process, including key cellular and humoral components. Despite this, the management and successful treatment of diabetic wounds represents a significant therapeutic challenge. To this end, the development of novel therapies and biological dressings has gained increased interest. Here we review key differences between normal and chronic non-healing diabetic wounds, and elaborate on recent advances in wound healing treatments with a particular focus on biological dressings and their effect on key wound healing pathways.
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http://dx.doi.org/10.3390/cells10030655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001234PMC
March 2021

Old Friends with Unexploited Perspectives: Current Advances in Mesenchymal Stem Cell-Based Therapies in Asthma.

Stem Cell Rev Rep 2021 Mar 1. Epub 2021 Mar 1.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Białystok, Poland.

Mesenchymal stem cells (MSCs) have a great regenerative and immunomodulatory potential that was successfully tested in numerous pre-clinical and clinical studies of various degenerative, hematological and inflammatory disorders. Over the last few decades, substantial immunoregulatory effects of MSC treatment were widely observed in different experimental models of asthma. Therefore, it is tempting to speculate that stem cell-based treatment could become an attractive means to better suppress asthmatic airway inflammation, especially in subjects resistant to currently available anti-inflammatory therapies. In this review, we discuss mechanisms accounting for potent immunosuppressive properties of MSCs and the rationale for their use in asthma. We describe in detail an intriguing interplay between MSCs and other crucial players in the immune system as well as lung microenvironment. Finally, we reveal the potential of MSCs in maintaining airway epithelial integrity and alleviating lung remodeling.
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http://dx.doi.org/10.1007/s12015-021-10137-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919631PMC
March 2021

Altered microRNA dynamics in acute coronary syndrome.

Postepy Kardiol Interwencyjnej 2020 Sep 2;16(3):287-293. Epub 2020 Oct 2.

Department of Cardiology, Medical University of Bialystok, Bialystok, Poland.

Introduction: In the course of acute myocardial infarction (AMI) cardiomyocyte injury, activation and destruction of endothelial cells together with inflammation lead to miRNA expression alterations.

Aim: To assess levels of circulating cardiac-specific (miR-1) and endothelial-specific (miR-126) miRNAs in the acute phase of AMI and after a follow-up period.

Material And Methods: Seventeen AMI patients (mean age: 64.24 ±13.83 years, mean left ventricle ejection fraction (LVEF): 42.6 ±9.65%), treated with primary percutaneous coronary intervention within the first 12 h, had plasma miRNAs isolated (quantitative real-time PCR, Exiqon) on admission and after 19.2 ±5.9 weeks. Measurements were also performed in a control group of healthy volunteers matched for age and sex.

Results: Concentrations of both miRNAs were significantly higher in AMI patients as compared to healthy controls: miR-1: 5.93 (3.15-14.92) vs. 1.46 (0.06-2.96), = 0.04; miR-126: 4.5 (3.11-7.64) vs. 0.54 (0.36-0.99), = 0.00003, respectively. Levels of both miRNAs significantly decreased after the follow-up period: miR-1: 5.93 (3.15-14.92) vs. 1.34 (0.04-2.34), = 0.002; miR-126: 4.5 (3.11-7.64) vs. 1.18 (0.49-1.68), = 0.0005). Moreover, miR-1 correlated positively with maximal troponin I concentration ( = 0.59, = 0.02) and negatively with LVEF ( = -0.76, = 0.0004).

Conclusions: In our study, miR-1 emerged as a marker of cardiomyocyte injury and loss of myocardial contractility, whereas dynamics of miR-126 concentration may reflect endothelial activation and damage in the most extreme stage of atherosclerosis, followed by angiogenesis in ischemic myocardium. However, to fully elucidate the role of miR-1 and miR-126 as biomarkers of AMI and future therapeutic targets, further research is required.
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http://dx.doi.org/10.5114/aic.2020.99263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863810PMC
September 2020

Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen-specific immunotherapy.

J Allergy Clin Immunol 2020 Oct 9. Epub 2020 Oct 9.

Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland; Christine Kühne-Center for Allergy Research and Education, Davos, Switzerland. Electronic address:

Background: Despite the efficacy of allergen-specific immunotherapy (AIT), the role of trained immunity and tolerance in this process has not been elucidated.

Objective: Here, we have performed a comprehensive longitudinal analysis of the systemic innate immune cell repertoire during the course of AIT.

Methods: Patients with allergy received standard preseasonal subcutaneous AIT with allergoids to birch and/or grass. Healthy controls were monitored without any intervention. Flow cytometry of innate lymphoid cell (ILC), natural killer cell, monocyte cell, and dendritic cell (DC) subsets was performed at baseline, 3 months (birch season), 6 months (grass seasons), and 12 months after the therapy in patients or at similar seasonal time points in controls. Additional analyses were performed in the third-year birch and grass season.

Results: We observed a durable decrease in group 2 ILCs and an increase of group 1 ILCs after AIT, with dynamic changes in their composition. We found that an expansion of CD127CD25 clusters caused observed shifts in the heterogeneity of group 1 ILCs. In addition, we observed development of CD127CD25c-Kit group 3 ILC clusters. Moreover, we found an increase in the number of intermediate monocytes in parallel with a reduction in nonclassical monocytes during the first year after AIT. Classical and intermediate monocytes presented significant heterogeneity in patients with allergy, but AIT reduced the HLA-DR clusters. Finally, an increase in plasmacytoid DCs and CD141 myeloid DCs was observed in individuals with allergy, whereas the number of CD1c myeloid DCs was reduced during the first year of AIT.

Conclusion: AIT induces changes in the composition and heterogeneity of circulating innate immune cells and brings them to the level observed in healthy individuals. Monitoring of ILCs, monocytes, and DCs during AIT might serve as a novel biomarker strategy.
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http://dx.doi.org/10.1016/j.jaci.2020.08.042DOI Listing
October 2020

Immunology of COVID-19: Mechanisms, clinical outcome, diagnostics, and perspectives-A report of the European Academy of Allergy and Clinical Immunology (EAACI).

Allergy 2020 10;75(10):2445-2476

Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

With the worldwide spread of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulting in declaration of a pandemic by the World Health Organization (WHO) on March 11, 2020, the SARS-CoV-2-induced coronavirus disease-19 (COVID-19) has become one of the main challenges of our times. The high infection rate and the severe disease course led to major safety and social restriction measures worldwide. There is an urgent need of unbiased expert knowledge guiding the development of efficient treatment and prevention strategies. This report summarizes current immunological data on mechanisms associated with the SARS-CoV-2 infection and COVID-19 development and progression to the most severe forms. We characterize the differences between adequate innate and adaptive immune response in mild disease and the deep immune dysfunction in the severe multiorgan disease. The similarities of the human immune response to SARS-CoV-2 and the SARS-CoV and MERS-CoV are underlined. We also summarize known and potential SARS-CoV-2 receptors on epithelial barriers, immune cells, endothelium and clinically involved organs such as lung, gut, kidney, cardiovascular, and neuronal system. Finally, we discuss the known and potential mechanisms underlying the involvement of comorbidities, gender, and age in development of COVID-19. Consequently, we highlight the knowledge gaps and urgent research requirements to provide a quick roadmap for ongoing and needed COVID-19 studies.
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http://dx.doi.org/10.1111/all.14462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361752PMC
October 2020

Obesity and disease severity magnify disturbed microbiome-immune interactions in asthma patients.

Nat Commun 2019 12 13;10(1):5711. Epub 2019 Dec 13.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

In order to improve targeted therapeutic approaches for asthma patients, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as obese asthmatics or severe asthmatics, are required. Here we report immunological and microbiome alterations in obese asthmatics (n = 50, mean age = 45), non-obese asthmatics (n = 53, mean age = 40), obese non-asthmatics (n = 51, mean age = 44) and their healthy counterparts (n = 48, mean age = 39). Obesity is associated with elevated proinflammatory signatures, which are enhanced in the presence of asthma. Similarly, obesity or asthma induced changes in the composition of the microbiota, while an additive effect is observed in obese asthma patients. Asthma disease severity is negatively correlated with fecal Akkermansia muciniphila levels. Administration of A. muciniphila to murine models significantly reduces airway hyper-reactivity and airway inflammation. Changes in immunological processes and microbiota composition are accentuated in obese asthma patients due to the additive effects of both disease states, while A. muciniphila may play a non-redundant role in patients with a severe asthma phenotype.
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http://dx.doi.org/10.1038/s41467-019-13751-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911092PMC
December 2019

Lower proportion of CD19IL-10 and CD19CD24CD27 but not CD1dCD5CD19CD24CD27 IL-10 B cells in children with autoimmune thyroid diseases.

Autoimmunity 2020 02 2;53(1):46-55. Epub 2019 Dec 2.

Department of Pediatric Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Bialystok, Poland.

As it is generally known, regulatory B cells (Bregs) control inflammation and autoimmunity. The significance of Bregs in the population of children with autoimmune thyroid diseases (AITD) still offers plenty of potential to explore. The aim of this study was to estimate the expression of Bregs (phenotype CD19CD24CD27IL-10, CD19IL-10, CD1dCD5CD19IL-10 and CD1dCD5CD19CD24CD27) in a paediatric cohort with AITD and in health controls. A total of 100 blood samples were obtained from 53 paediatric patients with Graves' disease (GD) ( = 12 newly diagnosed, mean age 12.5 ± 3.5 and  = 17 during methimazole therapy, mean age 12.7 ± 4.4), Hashimoto's thyroiditis (HT) ( = 10 newly diagnosed, mean age 13.3 ± 2.9 and  = 10 during L-thyroxine therapy, mean age 13.7 ± 3.4) and compared with healthy controls (C) ( = 15, mean age 13.1 ± 3.1). The expressions of the immune cell populations were analysed by four-color flow cytometry using a FASC Canto II cytometer (BD Biosciences). There was a decreasing tendency in the number of lymphocytes B producing IL-10 (B10) cells among all B lymphocytes and more widely, also among all lymphocytes, in each study group, as compared to C. We reported a reduction in IL-10 production in Bregs with the expression of CD19CD24CD27IL-10 and CD1dCD5CD19IL-10 in both untreated and treated AITD. Our data demonstrate that the reduction in the number of Bregs with CD19CD24CD27IL-10 and CD19IL-10 expression could be responsible for breaking immune tolerance and for AITD development in children.
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http://dx.doi.org/10.1080/08916934.2019.1697690DOI Listing
February 2020

Selected commensal bacteria change profiles of Helicobacter pylori-induced T cells via dendritic cell modulation.

Helicobacter 2019 Dec 21;24(6):e12614. Epub 2019 Jul 21.

Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

Background: The mechanisms of downregulation of protective immunity against Helicobacter pylori (Hp) infection strongly depend on dendritic cell (DC)-induced T-lymphocyte differentiation pattern. Lactic acid bacteria (LAB) strains can modulate Hp-induced immunoresponse by changes in DC activation profiles. Here, we want to find out if the LAB-pulsed DCs will change Hp-induced T-cell responsiveness patterns.

Materials And Methods: The naive peripheral CD4 T cells were co-cultured with Hp CagA + pulsed monocyte-derived DCs (DC/CD4 T cell) in the presence/absence of the feces-derived probiotics: antagonistic or non-antagonistic to Hp (Lactobacillus rhamnosus 900, Lr, Lactobacillus paracasei 915, Lp, respectively), as assessed by the agar slab method. The regulatory T-cell (Treg) population was assessed by flow cytometry, and IFN-γ, IL-12p70, IL-10, and IL-17A levels were evaluated by ELISA method.

Results: The Hp-pulsed DC/CD4 T-cell co-cultures were characterized by high IL-10, decreased IL-12p70 and IFN-γ levels, and elevated Treg population. In contrast, Lr-pulsed DC/CD4 T-cell co-cultures expressed low IL-10, high IL-12p70 and IFN-γ levels and declined Treg population; this responsiveness pattern was not changed by Hp. The responsiveness pattern of the Lp/Hp-pulsed DC/CD4 T-cell co-cultures did not differ from those pulsed with Hp alone.

Conclusion: In contrast to Lp, Lr probiotic strain overcomes Hp-mediated immune profile in the DC/T-cell co-cultures toward Th1 pattern and limited generation of Tregs in vitro. Lr may therefore be used as a component of anti-Hp treatment.
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http://dx.doi.org/10.1111/hel.12614DOI Listing
December 2019

Laundry detergents and detergent residue after rinsing directly disrupt tight junction barrier integrity in human bronchial epithelial cells.

J Allergy Clin Immunol 2019 05 27;143(5):1892-1903. Epub 2018 Nov 27.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, and the Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. Electronic address:

Background: Defects in the epithelial barrier have recently been associated with asthma and other allergies. The influence of laundry detergents on human bronchial epithelial cells (HBECs) and their barrier function remain unknown.

Objective: We investigated the effects of laundry detergents on cytotoxicity, barrier function, the transcriptome, and the epigenome in HBECs.

Methods: Air-liquid interface cultures of primary HBECs from healthy control subjects, patients with asthma, and patients with chronic obstructive pulmonary disease were exposed to laundry detergents and detergent residue after rinsing. Cytotoxicity and epithelial barrier function were evaluated. RNA sequencing, Assay for Transposase Accessible Chromatin with high-throughput sequencing, and DNA methylation arrays were used for checking the transcriptome and epigenome.

Results: Laundry detergents and rinse residue showed dose-dependent toxic effects on HBECs, with irregular cell shape and leakage of lactate dehydrogenase after 24 hours of exposure. A disrupted epithelial barrier function was found with decreased transepithelial electrical resistance, increased paracellular flux, and stratified tight junction (TJ) immunostaining in HBECs exposed to laundry detergent at 1:25,000 dilutions or rinse residue at further 1:10 dilutions. RNA sequencing analysis showed that lipid metabolism, apoptosis progress, and epithelially derived alarmin-related gene expression were upregulated, whereas cell adhesion-related gene expression was downregulated by laundry detergent at 1:50,000 dilutions after 24 hours of exposure without substantially affecting chromatin accessibility and DNA methylation.

Conclusion: Our data demonstrate that laundry detergents, even at a very high dilution, and rinse residue show significant cell-toxic and directly disruptive effects on the TJ barrier integrity of HBECs without affecting the epigenome and TJ gene expression.
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http://dx.doi.org/10.1016/j.jaci.2018.11.016DOI Listing
May 2019

The relationships among monocyte subsets, miRNAs and inflammatory cytokines in patients with acute myocardial infarction.

Pharmacol Rep 2019 Feb 12;71(1):73-81. Epub 2018 Sep 12.

Department of Cardiology, Medical University of Bialystok, Białystok, Poland. Electronic address:

Background: Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF-α and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI.

Methods: In eighteen consecutive AMI patients (mean age 56.78 ± 12.4 years, mean left ventricle ejection fraction - LVEF: 41.9 ± 9.8%), treated invasively, monocyte subsets frequencies were evaluated (flow cytometry), cytokine concentrations were analyzed (ELISA) as well as plasma miRNAs were isolated twice - on admission and after 19.2 ± 5.9 weeks of follow-up. Measurements were also performed among healthy volunteers.

Results: AMI patients presented significantly decreased frequencies of classical cells in comparison to healthy controls (median 71.22% [IQR: 64.4-79.04] vs. 84.35% [IQR: 81.2-86.7], p = 0.001) and higher percent of both intermediate and non-classical cells, yet without statistical significance (median 6.54% [IQR: 5.14-16.64] vs. 5.87% [IQR: 4.48-8.6], p = 0.37 and median 5.99% [IQR: 3.39-11.5] vs. 5.26% [IQR: 3.62-6.2], p = 0.42, respectively). In AMI patients both, analyzed plasma miRNA concentrations were higher than in healthy subjects (miR-146: median 5.48 [IQR: 2.4-11.27] vs. 1.84 [IQR: 0.87-2.53], p = 0.003; miR-155: median 25.35 [IQR: 8.17-43.15] vs. 8.4 [IQR: 0.08-16.9], p = 0.027, respectively), and returned back to the values found in the control group in follow-up. miR-155/miR-146 ratio correlated with the frequencies of classical monocytes (r=0.6, p = 0.01) and miR-155 correlated positively with the concentration of inflammatory cytokines - IL-6 and TNF-α.

Conclusions: These results may suggest cooperation of both pro-inflammatory and anti-inflammatory signals in AMI in order to promote appropriate healing of the infarcted myocardium.
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http://dx.doi.org/10.1016/j.pharep.2018.09.007DOI Listing
February 2019

Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice.

Allergy 2019 02 5;74(2):294-307. Epub 2018 Nov 5.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

Background: Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed.

Methods: We developed mouse models representing three different phenotypes of allergic airway inflammation-eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT-PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air-liquid interface were used to study the mechanisms revealed in the in vivo models.

Results: By whole-genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome-related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo-1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation. Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1, and IL-1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine-IL-1β-may transiently impair epithelial barrier function, while IL-1β and IL-17 increase mucin expressions in primary human bronchial epithelial cells.

Conclusion: Our findings suggest that differential expression of TJ, mucin, and inflammasome-related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic.
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http://dx.doi.org/10.1111/all.13619DOI Listing
February 2019

Very Small Embryonic-Like Stem Cells, Endothelial Progenitor Cells, and Different Monocyte Subsets Are Effectively Mobilized in Acute Lymphoblastic Leukemia Patients after G-CSF Treatment.

Stem Cells Int 2018 21;2018:1943980. Epub 2018 Jun 21.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Ul. Waszyngtona 13, 15-269 Bialystok, Poland.

Background: Acute lymphoblastic leukemia (ALL) is a malignant disease of lymphoid progenitor cells. ALL chemotherapy is associated with numerous side effects including neutropenia that is routinely prevented by the administration of growth factors such as granulocyte colony-stimulating factor (G-CSF). To date, the effects of G-CSF treatment on the level of mobilization of different stem and progenitor cells in ALL patients subjected to clinically effective chemotherapy have not been fully elucidated. Therefore, in this study we aimed to assess the effect of administration of G-CSF to ALL patients on mobilization of other than hematopoietic stem cell (HSCs) subsets, namely, very small embryonic-like stem cells (VSELs), endothelial progenitor cells (EPCs), and different monocyte subsets.

Methods: We used multicolor flow cytometry to quantitate numbers of CD34+ cells, hematopoietic stem cells (HSCs), VSELs, EPCs, and different monocyte subsets in the peripheral blood of ALL patients and normal age-matched blood donors.

Results: We showed that ALL patients following chemotherapy, when compared to healthy donors, presented with significantly lower numbers of CD34+ cells, HSCs, VSELs, and CD14+ monocytes, but not EPCs. Moreover, we found that G-CSF administration induced effective mobilization of all the abovementioned progenitor and stem cell subsets with high regenerative and proangiogenic potential.

Conclusion: These findings contribute to better understanding the beneficial clinical effect of G-CSF administration in ALL patients following successful chemotherapy.
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http://dx.doi.org/10.1155/2018/1943980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032642PMC
June 2018

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy.

Stem Cell Rev Rep 2018 Oct;14(5):686-693

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Bialystok, Poland.

IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN.
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http://dx.doi.org/10.1007/s12015-018-9840-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132770PMC
October 2018

Gastric cancer increases transmigratory potential of peripheral blood monocytes by upregulation of β1- and β2-integrins.

Contemp Oncol (Pozn) 2018 Mar 5;22(1A):33-37. Epub 2018 Mar 5.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Poland.

Introduction: Immune responses within the tumor depend on the ability of leukocytes to migrate from peripheral circulation into the local microenvironment. This process is controlled by mechanisms that guide leukocytes to the side of inflammation, allowing them to cross vascular endothelial barrier. Monocytes/macrophages are the predominant population of leukocyte infiltrate of many tumors, including, gastric cancer. However, to date mechanisms that control monocyte trafficking to the side of tumor growth are not fully elucidated.

Aim Of The Study: It this study we aimed to evaluate transmigratory potential of peripheral blood monocytes from gastric cancer patients.

Material And Methods: By using multicolor flow cytometry we assessed expression of β1- and β2-integrins on peripheral blood monocytes from gastric cancer patients.

Results: We found increased frequencies of VLA-4 and VLA-6 expressing monocytes and increased expression of analyzed β2-integrins in gastric cancer patients when compared to age matched controls.

Conclusions: In summary, this study revealed that gastric cancer increases transmigratory potential of peripheral blood monocytes.
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http://dx.doi.org/10.5114/wo.2018.73881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885073PMC
March 2018

Prognostic significance of Notch ligands in patients with non-small cell lung cancer.

Oncol Lett 2017 Jan 23;13(1):506-510. Epub 2016 Nov 23.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland.

The Notch signaling pathway is deregulated in numerous solid types of cancer including non-small cell lung cancer (NSCLC). However, the profile of Notch ligand expression remains unclear. Therefore, the present study aimed to determine the profile of Notch ligands in NSCLC patients and to investigate whether quantitative assessment of Notch ligand expression may have prognostic significance in NSCLC patients. The study was performed in 61 pairs of tumor and matched unaffected lung tissue specimens obtained from patients with various stages of NSCLC, which were analyzed by reverse transcription-polymerase chain reaction. The marked expression levels of certain analyzed genes were detected in NSCLC samples and in noncancerous lung samples. Of the five Notch ligands, jagged 1 (), jagged 2, delta-like protein 1 and delta-like protein 4 were expressed in the majority of tissues, but their expression levels were reduced in NSCLC when compared with noncancerous lung tissue (P<0.001). Delta-like protein 3 expression was consistently low and was observed only in 21/61 tumor tissue samples. Taken together, Notch ligands are expressed in NSCLC. However, the expression level is reduced when compared to noncancerous tissue. Furthermore, the present study revealed that quantitative assessment of expression in NSCLC may improve prognostication of patient survival.
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http://dx.doi.org/10.3892/ol.2016.5420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244844PMC
January 2017

Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia.

J Cancer 2016 30;7(14):1979-1983. Epub 2016 Sep 30.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Poland.

B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), two members of the tumour necrosis factor (TNF) superfamily, beyond playing a significant role in normal B-cell development, promote survival and proliferation of malignant B cells. Both ligands interact with 3 receptors: BAFF-R, specific to BAFF, and TACI and BCMA which are shared by both BAFF and APRIL. Here we wished to investigate the potential role of these proteins in resistance of acute myeloid leukaemia (AML) blasts to apoptosis. We found that the levels of both mRNA and proteins of APRIL, BAFF and their receptors were expressed in leukaemic cells of 24 newly diagnosed, untreated AML patients. We also demonstrated that patients who did not further respond to induction therapy (NR) presented with significantly higher baseline APRIL and BAFF expression on AML blasts as compared to these subjects who, after induction, achieved complete remission (CR) following induction therapy. Moreover, we observed striking differences in baseline levels of BCMA between CR and NR patients as we did not find detectable expression of this receptor in the latter group of patients. Interestingly, we found that AML blasts collected at baseline from NR patients cultured in presence of exogenous BAFF and APRIL were significantly more resistant to spontaneous or drug-induced apoptosis as compared with cells derived from CR patients. Altogether, our data confirm that BAFF and APRIL signaling play important role in AML pathogenesis and susceptibility to cytotoxic therapy while measuring of BCMA expression on AML cells can become a novel prognostic factor for chemotherapy response.
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http://dx.doi.org/10.7150/jca.15966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118661PMC
September 2016

Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases.

J Allergy Clin Immunol 2016 10 28;138(4):984-1010. Epub 2016 Aug 28.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.

There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.
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http://dx.doi.org/10.1016/j.jaci.2016.06.033DOI Listing
October 2016

Effect of Periodic Granulocyte Colony-Stimulating Factor Administration on Endothelial Progenitor Cells and Different Monocyte Subsets in Pediatric Patients with Muscular Dystrophies.

Stem Cells Int 2016 6;2016:2650849. Epub 2015 Dec 6.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland; Department of Allergology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland.

Muscular dystrophies (MD) are heterogeneous group of diseases characterized by progressive muscle dysfunction. There is a large body of evidence indicating that angiogenesis is impaired in muscles of MD patients. Therefore, induction of dystrophic muscle revascularization should become a novel approach aimed at diminishing the extent of myocyte damage. Recently, we and others demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) resulted in clinical improvement of patients with neuromuscular disorders. To date, however, the exact mechanisms underlying these beneficial effects of G-CSF have not been fully understood. Here we used flow cytometry to quantitate numbers of CD34+ cells, endothelial progenitor cells, and different monocyte subsets in peripheral blood of pediatric MD patients treated with repetitive courses of G-CSF administration. We showed that repetitive cycles of G-CSF administration induced efficient mobilization of above-mentioned cells including cells with proangiogenic potential. These findings contribute to better understanding the beneficial clinical effects of G-CSF in pediatric MD patients.
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http://dx.doi.org/10.1155/2016/2650849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684893PMC
January 2016

Enhanced pretreatment CD25 expression on peripheral blood CD4+ T cell predicts shortened survival in acute myeloid leukemia patients receiving induction chemotherapy.

Pharmacol Rep 2016 Feb 10;68(1):12-9. Epub 2015 Jun 10.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Białystok, Poland; Department of Allergology and Internal Medicine, Medical University of Bialystok, Białystok, Poland. Electronic address:

Background: Recently, identification of CD25 (interleukin-2 receptor alpha) expression on leukemic blasts was correlated to early treatment failure and unfavorable outcome in acute myeloid leukemia (AML) patients. Here we wished to determine whether quantification of CD25 on peripheral blood CD4+ T cells could improve prognostication in newly diagnosed AML patients.

Methods: The mean fluorescence intensity (MFI) of CD25 expression and frequencies of peripheral blood CD4+ T cells with varying levels of CD25 and CD127 expression were assessed by flow cytometry in all studied individuals.

Results: Using univariate (unadjusted) and multivariate (adjusted) analyses we demonstrated that detection of high pretreatment CD25 expression on circulating CD4+ T cells was associated with significantly decreased survival rate of AML patients subjected to standard induction chemotherapy. These associations held true for both entire group of analyzed AML patients and different subgroups of patients identified by presence or absence of favorable and adverse molecular prognostic factors.

Conclusions: Our data indicate that quantification of CD25 expression on peripheral blood CD4+ T cells could become a novel, easily accessible method of shortened survival prognostication of AML patients subjected to standard cytotoxic therapy.
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http://dx.doi.org/10.1016/j.pharep.2015.05.025DOI Listing
February 2016

Phenotype of NK Cells Determined on the Basis of Selected Immunological Parameters in Children Treated due to Acute Lymphoblastic Leukemia.

Medicine (Baltimore) 2015 Dec;94(52):e2369

From the Departments of Pediatrics, Hematology and Oncology; and Immunology (SK, RD, AK, EG, BT, AE, LG, MK, BK, BK-R, IK, M Wiese, MJ, JM, M Wysocki, JS), Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland, and Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland (GG).

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. The chemotherapy for ALL is associated with a profound secondary immune deficiency.We evaluated the number and phenotype of natural killer (NK) cells at diagnosis, after the intensive chemotherapy and following the completion of the entire treatment for patients with ALL. The fraction, absolute number, and percentage of NK cells expressing interferon-γ were determined in full blood samples. The fraction of NK cells expressing CD158a, CD158b, perforin, A, B, and K granzymes was examined in isolated NK cells.We have shown that patients assessed at ALL diagnosis showed significantly lower values of the fraction of NK cells and percentage of NK cells with the granzyme A expression. Additionally, the absolute number of NK cells, the expression of CD158a, CD158b, perforin, and granzyme A were significantly lower in patients who completed intensive chemotherapy. Also, there was a significantly higher fraction of NK cells expressing granzyme K in patients who completed the therapy.Abnormalities of NK cells were found at all stages of the treatment; however, the most pronounced changes were found at the end of intensive chemotherapy.
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http://dx.doi.org/10.1097/MD.0000000000002369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291621PMC
December 2015

Novel evidence that pituitary gonadotropins directly stimulate human leukemic cells-studies of myeloid cell lines and primary patient AML and CML cells.

Oncotarget 2016 Jan;7(3):3033-46

Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, KY, USA.

We recently reported that normal hematopoietic stem cells express functional pituitary sex hormone (SexH) receptors. Here we report for the first time that pituitary-secreted gonadotrophins stimulate migration, adhesion, and proliferation of several human myeloid and lymphoid leukemia cell lines. Similar effects were observed after stimulation of human leukemic cell lines by gonadal SexHs. This effect seems to be direct, as the SexH receptors expressed by leukemic cells responded to stimulation by phosphorylation of MAPKp42/44 and AKTser473. Furthermore, in parallel studies we confirmed that human primary patient-derived AML and CML blasts also express several functional SexH receptors. These results shed more light on the potential role of SexHs in leukemogenesis and, in addition, provide further evidence suggesting a developmental link between hematopoiesis and the germline.
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http://dx.doi.org/10.18632/oncotarget.6698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823088PMC
January 2016

Effective Mobilization of Very Small Embryonic-Like Stem Cells and Hematopoietic Stem/Progenitor Cells but Not Endothelial Progenitor Cells by Follicle-Stimulating Hormone Therapy.

Stem Cells Int 2016 9;2016:8530207. Epub 2015 Nov 9.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, 15-269 Bialystok, Poland ; Department of Allergology and Internal Medicine, Medical University of Bialystok, 15-276 Bialystok, Poland.

Recently, murine hematopoietic progenitor stem cells (HSCs) and very small embryonic-like stem cells (VSELs) were demonstrated to express receptors for sex hormones including follicle-stimulating hormone (FSH). This raised the question of whether FSH therapy at clinically applied doses can mobilize stem/progenitor cells in humans. Here we assessed frequencies of VSELs (referred to as Lin(-)CD235a(-)CD45(-)CD133(+) cells), HSPCs (referred to as Lin(-)CD235a(-)CD45(+)CD133(+) cells), and endothelial progenitor cells (EPCs, identified as CD34(+)CD144(+), CD34(+)CD133(+), and CD34(+)CD309(+)CD133(+) cells) in fifteen female patients subjected to the FSH therapy. We demonstrated that FSH therapy resulted in statistically significant enhancement in peripheral blood (PB) number of both VSELs and HSPCs. In contrast, the pattern of responses of EPCs delineated by different cell phenotypes was not uniform and we did not observe any significant changes in EPC numbers following hormone therapy. Our data indicate that FSH therapy mobilizes VSELs and HSPCs into peripheral blood that on one hand supports their developmental origin from germ lineage, and on the other hand FSH can become a promising candidate tool for mobilizing HSCs and stem cells with VSEL phenotype in clinical settings.
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http://dx.doi.org/10.1155/2016/8530207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655290PMC
December 2015

Differentiation of morphotic elements in human blood using optical coherence tomography and a microfluidic setup.

Opt Express 2015 Oct;23(21):27724-38

We demonstrate a novel optical method for the detection and differentiation between erythrocytes and leukocytes that uses amplitude and phase information provided by optical coherence tomography (OCT). Biological cells can introduce significant phase modulation with substantial scattering anisotropy and dominant forward-scattered light. Such physical properties may favor the use of a trans-illumination imaging technique. However, an epi-illumination mode may be more practical and robust in many applications. This study describes a new way of measuring the phase modulation introduced by flowing microobjects. The novel part of this invention is that it uses the backscattered signal from the substrate located below the flowing/moving objects. The identification of cells is based on phase-sensitive OCT signals. To differentiate single cells, a custom-designed microfluidic device with a highly scattering substrate is introduced. The microchannels are molded in polydimethylsiloxane (PDMS) mixed with titanium dioxide (TiO2) to ensure high scattering properties. The statistical parameters of the measured signal depend on the cells' features, such as their size, shape, and internal structure.
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http://dx.doi.org/10.1364/OE.23.027724DOI Listing
October 2015

Differentiating between benign and malignant adnexal lesions with contrast-enhanced transvaginal ultrasonography.

Int J Gynaecol Obstet 2015 Nov 26;131(2):147-51. Epub 2015 Jul 26.

Department and Clinic of Obstetrics, Gynecology, and Oncological Gynecology, Dr Jan Biziel University Hospital, Bydgoszcz, Poland; Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.

Objective: To analyze the relationship between contrast kinetics in tumorous vessels and lesion histologic type in an attempt to differentiate between malignant and benign disease.

Methods: In a single-center prospective study, patients who had been referred for elective surgery because of a diagnosis of unilateral and/or bilateral adnexal masses were enrolled at Dr Jan Biziel University Hospital, Bydgoszcz, Poland, between January 2012 and September 2013. Participants underwent contrast-enhanced ultrasonography examination (CEUS). Contrast kinetics were obtained and compared with the neovascularization of the tumor. Accuracy, and positive and negative predictive values were calculated.

Results: Among 160 enrolled patients, 84 underwent CEUS examination and 51 lesions were studied. Baseline and maximum color Doppler intensities were significantly higher in malignant than in benign tumors (P < 0.001 for both). Similarly, the absolute and relative increases in color Doppler intensity were significantly higher in malignant tumors (P < 0.001). The estimated positive predictive value was 97.1%, the negative predictive value was 100%, and the accuracy was 100%. Peak enhanced intensity of fractional color Doppler Area and area under the time-intensity curve (S-parameter) correlated significantly with the histology of the lesion (P < 0.001). Probability curves demonstrated that higher S-parameter values were correlated with a higher risk of malignancy.

Conclusion: Transvaginal CEUS is a reliable and reproducible way to differentiate between benign and malignant adnexal lesions.
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http://dx.doi.org/10.1016/j.ijgo.2015.04.047DOI Listing
November 2015

Expression of Adiponectin Receptors on Peripheral Blood Leukocytes of Hypertensive Children Is Associated with the Severity of Hypertension.

Biomed Res Int 2015 4;2015:742646. Epub 2015 Jun 4.

Chair of Immunology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University of Torun, 85-094 Bydgoszcz, Poland ; Department of Microbiology and Immunology, The Children's Memorial Health Institute, 07-730 Warsaw, Poland.

The aim of the study was to find out whether peripheral blood leukocyte adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) protein expression patterns (flow cytometry) differ between the primary hypertension children (n = 57) and healthy controls (n = 19) and if their expression levels are related to selected clinical parameters. The group of 26 patients [AdipoR(-)] showed lower and the group of 31 patients [AdipoR(+)] showed higher AdipoRs protein expression than the control and each other (P < 0.01 for neutrophils, P < 0.05 for monocytes). The AdipoR(+) leukocytes expressed higher AdipoR1 mRNA levels (RT-PCR) than AdipoR(-) ones and controls (P = 0.022 and P = 0.007, resp.). Despite greater BMI, the AdipoR(-) patients had unchanged serum adiponectin levels. In contrast, AdipoR(+) patients had lower serum adiponectin concentrations than the AdipoR(-) ones and controls (P < 0.001). The AdipoR(+) patients had higher blood pressure (P = 0.042) and greater carotid intima-media thickness (P = 0.017) than the AdipoR(-) ones. The stage of hypertension was associated with increased neutrophil but not monocyte AdipoR1 density (AdipoR1 MFI) (P < 0.05). Severe ambulatory hypertension was presented more often in AdipoR(+) patients than in AdipoR(-) ones (51.6% versus 26.9%, resp.; P < 0.01). In conclusion, neutrophil AdipoRs upregulation was associated with early stages of vascular injury, hypertension severity, and low serum levels of adiponectin.
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http://dx.doi.org/10.1155/2015/742646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471253PMC
March 2016

Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia.

Pol Arch Med Wewn 2015 3;125(7-8):553-9. Epub 2015 Jul 3.

Introduction: Recent studies in a mouse model of chronic lymphocytic leukemia (CLL) demonstrated that inhibition of the programmed death receptor 1 (PD‑1)-PD‑L1 axis resulted in correction of leukemia‑induced CD8+ T cell‑related immune dysfunction and protected mice against CLL development. However, it remains unclear whether CLL development and progression can be also associated with CD4+ T cells expressing PD‑1.

Objectives: We aimed to analyze whether a quantitative assessment of CD4+PD‑1+ T cells performed at the time of diagnosis can have prognostic significance in patients with CLL.

Patients And Methods: We examined 56 patients with newly diagnosed CLL at different stages of the disease. The quantitative assessment of PD‑1‑expressing CD4+ T cells was performed in all patients, using multicolor flow cytometry.

Results: We demonstrated that CLL patients with an advanced (high and intermediate risk) stage had a significantly higher number of CD4+PD‑1+ T cells compared with subjects with low‑grade disease. Importantly, we showed that the number of PD‑1‑expressing CD4+ T cells in the peripheral blood of patients referred for immediate treatment due to the advanced stage of the disease was significantly higher compared with subjects on watchful waiting. Finally, we found that treatment‑naive patients with higher numbers of CD4+PD‑1+ T cells at baseline showed a significantly shortened time to the first treatment compared with patients with a low number of CD4+PD‑1+ T cells.

Conclusions: Our study showed that the quantative assessment of CD4+PD‑1+ T cells in peripheral blood using flow cytometry can facilitate prognostication of patients with newly diagnosed CLL.
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http://dx.doi.org/10.20452/pamw.2967DOI Listing
February 2017

Circulating classical CD14++CD16- monocytes predict shorter time to initial treatment in chronic lymphocytic leukemia patients: Differential effects of immune chemotherapy on monocyte-related membrane and soluble forms of CD163.

Oncol Rep 2015 Sep 26;34(3):1269-78. Epub 2015 Jun 26.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland.

Three main monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++, differentially regulate tumor growth and survival. Thereby, in the present study we aimed to determine the role of distinct monocyte subsets in the prognostication of chronic lymphocytic leukemia (CLL). Moreover, we set out to analyze the effects of standard immune chemotherapy on different monocyte subsets and levels of membrane-associated and soluble forms of CD163, a monocyte/macrophage-related immunomodulatory protein. We demonstrated that the number of peripheral blood classical CD14++CD16- monocytes assessed at the time of diagnosis was negatively correlated with lymphocytosis and was decreased in the CLL patients who required immediate treatment as opposed to patients who qualified to 'watch and wait' strategy. Notably, lower baseline levels of classical CD14++CD16- monocytes in CLL patients who were qualified for 'watch and wait' therapy were associated with shorter time to initial treatment. Notably, therapy with rituximab, cyclophosphamide and fludarabine resulted in a significant reduction in the number of non-classical CD14+CD16++ monocytes and soluble form of CD163 but upregulation of membrane-associated monocyte CD163. Our data indicate that distinct monocyte subsets and two forms of CD163 are differentially modulated by both CLL and immune chemotherapy. Moreover, we proposed that quantification of classical monocytes at the time of diagnosis contributes to better prognostication of CLL patients.
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http://dx.doi.org/10.3892/or.2015.4088DOI Listing
September 2015

Synthesis and anti-inflammatory activity of new 1,2,4-triazole derivatives.

Bioorg Med Chem Lett 2015 Jul 30;25(13):2664-7. Epub 2015 Apr 30.

Department of Immunology, Faculty of Pharmacy, Nicolaus Copernicus University in Toruń, M. Sklodowskiej-Curie 9, 85-094 Bydgoszcz, Poland.

The series of new 1,2,4-triazole derivatives with methacrylic acid moiety were synthesized and characterized by NMR and IR spectroscopy as well as X-ray crystallography. The influence of newly synthesized compounds on the inflammation on the level of cytokine production and the proliferation of human peripheral blood mononuclear cells (PBMC) were experimentally evaluated. Obtained triazoles showed antiproliferative activity and diverse effects on cytokine production. Two compounds demonstrated potentially anti-inflammatory activity and comparable effects with ibuprofen.
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http://dx.doi.org/10.1016/j.bmcl.2015.04.079DOI Listing
July 2015

Vitamin D3 Treatment Decreases Frequencies of CD16-Positive and TNF-α-Secreting Monocytes in Asthmatic Patients.

Int Arch Allergy Immunol 2015 11;166(3):170-6. Epub 2015 Apr 11.

Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland.

Background: Previously, we demonstrated that glucocorticoid (GC) treatment of asthmatic patients resulted in decreasing frequencies of monocyte subsets expressing CD16 and capable of releasing TNF-α. Here, we wished to analyze whether the active form of vitamin D, i.e. vitamin D3, referred to as 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3] can exert GC-like proapoptotic effects on CD16-positive monocytes and thus decrease the proinflammatory potential of these cells. Finally, we set out to investigate whether the addition of 1,25-(OH)2D3 would facilitate the use of lower doses of GC without decreasing their anti-inflammatory properties.

Methods: Peripheral blood mononuclear cells collected from healthy individuals and asthmatic patients were cultured with 1,25-(OH)2D3 and/or varying doses of GC in the presence or absence of caspase inhibition. The cells were either directly stained for extracellular markers or prestimulated with lipopolysaccharide for the assessment of intracellular cytokine production and then analyzed by flow cytometry.

Results: We found that 1,25-(OH)2D3 alone (and in combination with GC) decreased the frequency of CD14++CD16+ and CD14+CD16++ monocytes from asthmatic patients and significantly diminished TNF-α production by the monocytes. With regard to the CD14+CD16++ subset, the monocyte-depleting effects of 1,25-(OH)2D3 were abrogated in the presence of pan-caspase inhibitor, suggesting a proapoptotic mechanism of 1,25-(OH)2D3 action. Interestingly, we found that a combined treatment of 1,25-(OH)2D3 and GC allowed for a 5-fold reduction of the GC dose while maintaining their anti-inflammatory effects.

Conclusions: This study has revealed novel immunomodulatory properties of 1,25-(OH)2D3 directed against monocyte subsets capable of TNF-α production. In addition, our data suggest that the introduction of 1,25-(OH)2D3 to anti-inflammatory therapy would possibly allow for the use of lower doses of GC.
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http://dx.doi.org/10.1159/000380882DOI Listing
July 2015