Publications by authors named "Amina Kariminia"

52 Publications

"Age Related Differences in the Biology of Chronic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation".

Front Immunol 2020 16;11:571884. Epub 2020 Oct 16.

Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

It is established that pediatric hematopoietic stem cell transplant (HSCT) recipients have a lower rate of chronic graft-versus-host disease (cGvHD) compared to adults. Our group has previously published immune profiles changes associated with cGvHD of clinically well-defined adult and pediatric HSCT cohorts. Since all analyses were performed by the same research group and analyzed using identical methodology, we first compared our previous immune profile analyses between adults and children. We then performed additional analyses comparing the T cell populations across age groups, and a sub-analysis of the impact of the estimated pubertal status at time of HSCT in our pediatric cohort. In all analyses, we corrected for clinical covariates including total body irradiation and time of onset of cGvHD. Three consistent findings were seen in both children and adults, including elevations of ST2 and naive helper T (Th) cells and depression of NK cells. However, significant differences exist between children and adults in certain cytokines, B cell, and T populations. In children, we saw a broad suppression of newly formed B (NF-B) cells, whereas adults exhibited an increase in T1-CD21 B cells and a decrease in T1-CD24CD38 B cells. Prepubertal children had elevations of aminopeptidase N (sCD13) and ICAM-1. T abnormalities in children appeared to be primarily in memory T cells, whereas in adults the abnormalities were in naïve T cells. In adults, the loss of PD1 expression in naïve T and naïve Th cells was associated with cGvHD. We discuss the possible mechanisms for these age-related differences, and how they might theoretically impact on different therapeutic approaches to cGvHD between children and adults.
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http://dx.doi.org/10.3389/fimmu.2020.571884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641628PMC
October 2020

In vitro and ex vivo anti-diabetic and anti-hyperglycemic properties of Zataria multiflora essential oil.

Mol Biol Rep 2020 Oct 1;47(10):7805-7813. Epub 2020 Oct 1.

Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

The underlying mechanism involved in the onset of many diseases such as diabetes is oxidative stress. Zataria multiflora has a very high antioxidant power that can be used in the antioxidant therapy of the diabetes symptom. The in vitro antioxidant and anti-diabetic capacity of Zataria multiflora essential oil (ZMEO) incorporated in dendrosome against glucose oxidation, lipid oxidation, protein oxidation, and protein glycation was analyzed. The ex vivo antioxidant capacity of dendrosomal ZMEO were explored against hyperglycemia (HG)-induced oxidative stress. Inhibition of oxidative stress markers; NADH oxidase (NOX), nuclear respiratory factor 2 (NRF2) and nuclear factor kappa B (NF-kB) were examined. Dendrosomal-ZMEO displayed low conductivity, low surface tension, low zeta-potential, nanoscale particle size and low viscosity that suggest dendrosomal-ZMEO could remain stable in biological fluids. FTIR spectra of dendrosomal-ZMEO indicated the non-covalent interactions between dendrosome and ZMEO and the entrapment of ZMEO droplets in the dendrosome network. Dendrosomal-ZMEO displayed good anti-glucose oxidation, anti-lipid peroxidation, anti-protein oxidation, and anti-protein glycation activity. Dendrosomal ZMEO strongly reduced intracellular hydrogen peroxide and NOX expression and activity in HG-treated macrophages while increased superoxide dismutase (SOD) and catalase (CAT) expression and activity in a synergistic manner. HG-treated murine macrophages showed an increased level of NF-kB expression while the decreased level of NRF2 expression compared to controls. The anti-diabetic activity of ZMEO by sequestering hydrogen peroxide and down-regulation of NOX activity is a recommended mechanism for diabetes and oxidative stress. The effect of ZMEO on decreasing NF-kB and increasing in NRF2, transcription factors involved in oxidative stress and hyperglycemia, may imply its clinical application.
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http://dx.doi.org/10.1007/s11033-020-05857-xDOI Listing
October 2020

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies.

Blood 2020 04;135(15):1287-1298

CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.
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http://dx.doi.org/10.1182/blood.2019003186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146024PMC
April 2020

A Germline Mutation in the C2 Domain of PLCγ2 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases.

J Clin Immunol 2020 02 19;40(2):267-276. Epub 2019 Dec 19.

Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada.

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2-knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to control-transfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects.
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http://dx.doi.org/10.1007/s10875-019-00731-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086538PMC
February 2020

Anti-Thymocyte Globulin Prophylaxis Induces a Decrease in Naive Th Cells to Inhibit the Onset of Chronic Graft-versus-Host Disease: Results from the Canadian Bone Marrow Transplant Group (CBMTG) 0801 Study.

Biol Blood Marrow Transplant 2020 03 19;26(3):438-444. Epub 2019 Nov 19.

Division of Pediatric Hematology/Oncology/Blood & Marrow Transplant, BC Children's Hospital, Vancouver, British Columbia, Canada; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada. Electronic address:

Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21 B cells, CD56 NK cells, and T cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56 NK cells (P < .0001). T cells, conventional Th cells, CD21 B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.
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http://dx.doi.org/10.1016/j.bbmt.2019.11.015DOI Listing
March 2020

The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study.

Pediatr Hematol Oncol 2019 Nov 18;36(8):468-481. Epub 2019 Sep 18.

Department of Pediatric Hematology, Oncology & BMT, University of British Columbia, Vancouver, USA.

: Preclinical studies show that TLR9 agonists can eradicate leukemia by induction of immune responses against AML and ALL. These studies demonstrated that TLR9 agonists induce an immediate NK response followed by adaptive T and B cells responses resulting in long term anti-leukemia immunity. : The Therapeutic Advances in Childhood Leukemia and Lymphoma Phase I consortium performed a pilot study on 3 patients with MRD positive acute leukemia after an initial remission on conventional chemotherapy (TACL T2009-008) with the TLR 9 agonist (GNKG168). To guide future trial development, we evaluated the impact of GNKG168 by Nanostring on the expression 608 genes before and 8 days after initiation of GNKG168 therapy. : Twenty-three out of 578 markers on the nanostring panel showed significant difference ( ≤ 0.05). We focused on 8 markers that had the greatest differences with  < 0.01. Two genes were increased, and , and 6 were decreased, and (). Tumor inhibitory pathways were downregulated including the (), important in signaling and NK cell inhibition. TLR9 can induce IL-33, which is known to downregulate ST2 (IL1RL1) a receptor for IL-33. : GNKG168 therapy is associated with immunologic changes in pediatric leukemia patients. Further work with a larger sample size is required to assess the impact of these changes on disease treatment and persistence of leukemia remission.
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http://dx.doi.org/10.1080/08880018.2019.1667461DOI Listing
November 2019

Circulating mesenchymal stem cells in sulfur mustard-exposed patients with long-term pulmonary complications.

Toxicol Lett 2019 Sep 13;312:188-194. Epub 2019 May 13.

Department of Biostatistics and Social Medicine, Zanjan University of Medical Sciences, Zanjan, Islamic Republic of Iran.

Sulfur mustard (SM) is a toxic agent that causes acute and long-term pulmonary complications. Recent evidence has shown the impact of SM on mesenchymal stem cells (MSCs). These cells have a critical role in repairing the damaged tissues. In this study, we evaluated the mobilization of MSCs in SM-exposed patients with long-term pulmonary complications. Fifty-nine SM-injured patients with prolonged pulmonary complications and 20 healthy individuals were included. Patients were classified based on taking drugs, having comorbidities, and severity of respiratory consequence. MSCs with phenotype of CD45-CD44CD29CD105 were evaluated in peripheral blood using flow cytometry. Circulating MSCs were lower in SM-exposed patients compared to the control group (0.93 vs. 2.72 respectively, P = 0.005). No significant difference was observed in the MSC count between patients taking corticosteroids or antibiotics and those patients not taking them. Comorbidities like liver and kidney diseases had changed the count of MSCs in SM-exposed subjects. In addition, the frequency of MSCs did not show any association with the severity of long-term pulmonary complications. In conclusion, SM-exposure causes a decline in the frequency of circulating MSCs in survivors. The lower number of the peripheral MSC population in SM-exposed patients was not affected by taking corticosteroids or antibiotics, but comorbidities are probably involved in MSC frequency. The decreases observed in the number of circulating MSCs was not associated with the severity of the pulmonary complications; however, further studies in mustard lung models are required to demonstrate the therapeutic or pathologic role of MSCs in SM injuries.
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http://dx.doi.org/10.1016/j.toxlet.2019.05.015DOI Listing
September 2019

Comprehensive B Cell Phenotyping Profile for Chronic Graft-versus-Host Disease Diagnosis.

Biol Blood Marrow Transplant 2019 03 14;25(3):451-458. Epub 2018 Nov 14.

Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada; Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, Canada. Electronic address:

Previous studies have reported single B cell-related chronic graft-versus-host disease diagnostic (cGVHD) biomarkers, such as B cell-activating factor (BAFF), CD21, and immature B cells, but research on the performance of biomarker combinations and the covariate effect of steroids is lacking. The primary objective of this study was to determine the most accurate combination of B cell populations using cell surface staining flow cytometry in an independent cohort of patients with cGVHD. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the makeup and accuracy of the diagnostic panel and identifying the mechanism underlying low surface expression of BAFF receptor (BAFF-R) on B cells in cGVHD. Flow cytometry analysis was performed in an adult cohort of post-HCT patients with cGVHD onset (n = 44) and time-matched recipients without cGVHD (n = 63). We confirmed that the onset of cGVHD was associated with higher soluble BAFF (sBAFF) levels, elevated CD27CD10CD21 CD19 B cell and classical switched memory B cell counts, and reduced transitional and naïve B cell counts. The highest single B cell population area under the receiver operating characteristic (ROC) curve (AUC) was .72 for transitional type 1 CD21 B cells. We also showed a significant inverse relationship between sBAFF and surface BAFF-R expression caused by sBAFF modulation of BAFF-R. Steroid use at sample collection influenced the significance of the sBAFF:B cell ratio, naïve and marginal zone-like B cells. The optimal combination of B cell subsets most significantly associated with cGVHD onset with or without concurrent corticosteroid use resulted in ROC AUCs of .87 and .84, respectively. Transitional and CD21 B cells were the only populations present in both panels; however, analyzing only these populations resulted in ROC AUCs of .79 and .78, respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. sBAFF was not a component of either panel. These novel B cell profiles could be tested prospectively in patients post-HSCT and could lead to focused mechanistic studies.
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http://dx.doi.org/10.1016/j.bbmt.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445755PMC
March 2019

Plerixafor effectively mobilizes CD56 NK cells in blood, providing an allograft predicted to protect against GVHD.

Blood 2018 06 4;131(25):2863-2866. Epub 2018 May 4.

Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, BC Children's Hospital, Vancouver, BC, Canada.

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http://dx.doi.org/10.1182/blood-2018-03-836700DOI Listing
June 2018

Higher levels of free plasma mitochondrial DNA are associated with the onset of chronic GvHD.

Bone Marrow Transplant 2018 10 21;53(10):1263-1269. Epub 2018 Mar 21.

Michael Cuccione Childhood Cancer Research Program, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.

Toll-like receptor-9 (TLR9) responsive B cells have previously been associated with the onset of extensive chronic graft-versus-host disease (cGvHD). We hypothesized that the onset of cGvHD associated with a higher level of plasma-free mitochondrial DNA (mtDNA), a putative TLR9 agonist. Plasma cell-free mtDNA levels were measured in 39 adult patients post-HSCT with and without cGvHD. mtDNA was isolated from plasma and quantified by Q-PCR amplification. We correlated B cell responsiveness to CpG-DNA, a prototypical TLR9 agonist, and previously identified cGVHD biomarkers with mtDNA levels. Free plasma mtDNA were elevated in patients post-HSCT without cGvHD compared to normal non-HSCT adults. There was a significantly higher level of free plasma mtDNA associated with the onset of cGvHD (3080 ± 1586 versus 1834 ± 1435 copies/μL; p = 0.02) compared to 6 months post-HSCT controls. Free mtDNA levels post-HSCT correlated with B cell responsiveness to CpG-DNA and known cGvHD biomarkers: CXCL10 (p = 0.003), ICAM-1 (p = 0.007), CXCL9 (p = 0.03), sCD25 (p = 0.05) and sBAFF (p = 0.05), and percentage of CD21 B cells. Plasma levels of free mtDNA are increased in cGvHD and may represent an endogenous inflammatory stimulus for TLR9 expressing B cells.
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http://dx.doi.org/10.1038/s41409-018-0156-yDOI Listing
October 2018

Absolute lymphocyte counts at end of induction correlate with distinct immune cell compartments in pediatric B cell precursor acute lymphoblastic leukemia.

Cancer Immunol Immunother 2018 02 20;67(2):225-236. Epub 2017 Oct 20.

Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, 950 West 28th Avenue, Reid Lab (Room 3062), Vancouver, BC, V5Z 4H4, Canada.

Several retrospective studies in children with B cell precursor (BCP) acute lymphoblastic leukemia (ALL) provided clinical evidence that higher absolute lymphocyte counts (ALC) early into treatment significantly correlated with improved relapse-free and overall survival. It still remains unknown, however, whether the predictive role of higher ALCs reflects general bone marrow recovery or a more specific attribute of immune function. To investigate this question, we implemented a prospective observational cohort study in 20 children with BCP ALL on day 29 (D29) of induction chemotherapy and immunophenotyped their lymphoid (T, B and natural killer cells) and myeloid (neutrophils, monocytes, dendritic cells) compartments. In a first evaluation of a cohort treated with Children's Oncology Group-based induction chemotherapy, the immune cell compartments were differentially depleted at D29. Neither gender, risk status, minimal residual disease, nor bone marrow recovery markers correlated with D29 ALC. In contrast, both CD3 T cell and dendritic cell compartments, which did not correlate with age, significantly correlated with D29 ALC (p < 0.0001). In addition, subset complexity of cellular immune compartments was preserved at D29. This study reveals that D29 ALC significantly correlates with distinct immune cell compartments but not with bone marrow recovery markers, suggesting that higher D29 ALCs may contribute to leukemia control by inducing specific host immune activity.
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http://dx.doi.org/10.1007/s00262-017-2070-3DOI Listing
February 2018

CD56 natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft--host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

Haematologica 2017 11 21;102(11):1936-1946. Epub 2017 Sep 21.

Michael Cuccione Childhood Cancer research Program, BC Children's Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada

Randomized trials have conclusively shown higher rates of chronic graft--host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft--host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft--host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft--host disease frequency was associated with lower proportions of CD56 natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56 natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft--host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56 natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56 natural killer regulatory cells results in the high rate of chronic graft--host disease seen in filgrastim-stimulated apheresis peripheral blood. .
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http://dx.doi.org/10.3324/haematol.2017.170928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664398PMC
November 2017

IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life.

Eur J Immunol 2017 05 11;47(5):892-899. Epub 2017 Apr 11.

Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.

The early-life immune environment has been implicated as a modulator of acute lymphoblastic leukemia (ALL) development in children, with infection being associated with significant changes in ALL risk. Furthermore, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Eμ-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-γ on the early-life burden of leukemia-initiating cells. The absence of IFN-γ activity resulted in greater numbers of leukemia-initiating cells early in life and was associated with accelerated leukemia onset. The leukemia-initiating cells from IFN-γ-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-γ, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-γ-knockout leukemia cells. These results demonstrate that the influence of IFN-γ on ALL progression may not be mediated by selection of nascent transformed cells but rather through a general SOCS-mediated reduction in B-cell precursor proliferation. Thus, while cytokine levels may influence leukemia at multiple points during disease progression, our study indicates a significant early influence of basal, infection-independent cytokine production on leukemogenesis.
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http://dx.doi.org/10.1002/eji.201646806DOI Listing
May 2017

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia.

Oncol Lett 2017 Jan 28;13(1):497-505. Epub 2016 Nov 28.

Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.

Y-box-binding protein 1 (YB-1) is a regulatory protein that is associated with drug resistance and relapse in solid tumors. As YB-1 mediates some of its activity through growth factor receptor signaling dysregulation, the present study compared the expression of YB-1 and interleukin 7 (IL-7) receptor α (IL-7Rα) in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) and normal BCP cells. The expression levels of IL-7Rα and YB-1 were higher in relapsed vs. diagnostic samples of primary BCP ALL; however, co-expression was also observed in a minor BCP cell population in samples from healthy donors. Functional crosstalk between YB-1 and IL-7R was detected: Overexpression of YB-1 increased surface levels of IL-7R in B cells, and the stimulation of BCP ALL cell lines and primary samples by IL-7 activated YB-1 by phosphorylation at S102 in a phosphatidylinositol 3-kinase-independent and MEK1/2-dependent manner. Targeted knockdown of YB-1 reduced IL-7-mediated protection against rapamycin, and an inhibitor of MEK1/2 potentiated rapamycin-mediated killing in the presence of IL-7. These data establish a novel link between two well-characterized pro-survival factors in acute leukemia, and suggest that YB-1 inhibition may represent a novel therapeutic strategy for increasing sensitivity to chemotherapy in patients with refractory acute B-cell leukemia.
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http://dx.doi.org/10.3892/ol.2016.5437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244896PMC
January 2017

Filgrastim-Stimulated Bone Marrow Compared with Filgrastim-Mobilized Peripheral Blood in Myeloablative Sibling Allografting for Patients with Hematologic Malignancies: A Randomized Canadian Blood and Marrow Transplant Group Study.

Biol Blood Marrow Transplant 2016 08 3;22(8):1410-1415. Epub 2016 May 3.

Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

In adult hematopoietic cell transplantation (HCT), filgrastim-mobilized peripheral blood (G-PB) has largely replaced unstimulated marrow for allografting. Although the use of G-PB results in faster hematopoietic recovery, it is also associated with more chronic graft-versus-host disease (cGVHD). A potential alternative allograft is filgrastim-stimulated marrow (G-BM), which we hypothesized may be associated with prompt hematopoietic recovery but with less cGVHD. We conducted a phase 3, open-label, multicenter randomized trial of 230 adults with hematologic malignancies receiving allografts from siblings after myeloablative conditioning to compare G-PB with G-BM. The primary endpoint was time to treatment failure, defined as a composite of extensive cGVHD, relapse/disease progression, and death. With a median follow-up of 36 months (range, 9.6 to 48), comparing G-BM with G-PB, there was no difference between the 2 arms with respect to the primary outcome of this study (hazard ratio [HR], .91; 95% confidence interval [CI], .68 to 1.22; P = .52). However, the cumulative incidence of overall cGVHD was lower with G-BM (HR, .66; 95% CI, .46 to .95; P = .007) and there was no difference in the risk of relapse or progression (P = .35). The median times to neutrophil recovery (P = .0004) and platelet recovery (P = .012) were 3 days shorter for recipients allocated to G-PB compared with those allocated to G-BM, but there were no differences in secondary engraftment-related outcomes, such as time to first hospital discharge (P = .17). In addition, there were no graft failures in either arm. This trial demonstrates that, compared with G-PB, the use of G-BM allografts leads to a significantly lower rate of overall cGVHD without a loss of the graft-versus-tumor effect and comparable overall survival. Our findings suggest that further study of this type of allograft is warranted.
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http://dx.doi.org/10.1016/j.bbmt.2016.04.017DOI Listing
August 2016

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells.

Blood 2016 06 28;127(24):3082-91. Epub 2016 Mar 28.

Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital/University of British Columbia, Vancouver, BC, Canada;

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.
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http://dx.doi.org/10.1182/blood-2015-09-668251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911864PMC
June 2016

Heterodimer-specific TLR2 stimulation results in divergent functional outcomes in B-cell precursor acute lymphoblastic leukemia.

Eur J Immunol 2015 Jul 6;45(7):1980-90. Epub 2015 May 6.

The Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute and Division of Pediatric Hem/Onc/BMT, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam3 CSK4 (TLR2/1), and Pam2 CSK4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam3 CSK4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam3 CSK4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.
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http://dx.doi.org/10.1002/eji.201444874DOI Listing
July 2015

Long term impact of sulfur mustard exposure on peripheral blood mononuclear subpopulations--Sardasht-Iran Cohort Study (SICS).

Int Immunopharmacol 2013 Nov 20;17(3):931-5. Epub 2013 Feb 20.

Immunoregulation Research Center, Shahed University, Tehran, Islamic Republic of Iran. Electronic address:

The most important long-term morbidity problem of sulfur mustard (SM) toxicity is pulmonary complications but the pathogenesis of these complications is not clearly understood. This study evaluates the peripheral blood mononuclear sub-sets and their correlation with pulmonary function in SM exposed civilian cases 20 years post-exposure as gathered in the context of the Sardasht-Iran Cohort Study (SICS). Samples were randomly selected from two groups, SM-exposed (n=372) and control (n=128), with the same ethnicity, culture, and demography. Three color flow cytometry was applied for peripheral blood mononuclear sub-population determination. Results indicated a significant decrease in CD45+/CD3+, CD45+/CD3+/CD4+, and an increase in CD3+/CD16+56+ percentages. It was also found that absolute count of NK cells was highly increased in peripheral blood of exposed cases. There was a significant increase in NK cell count of SM exposed group with pulmonary problems as compared to the same group without pulmonary problems (p-value<0.04) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The findings showed a significant negative correlation between absolute numbers of T lymphocyte and FVC % and positive correlation with FEV1/FVC%. The results also demonstrated that absolute numbers of monocytes had a negative correlation with FVC %. We propose that NK and T cells are probably involved in the pathogenesis or immune reactions to the delayed pulmonary complications induced by SM. This hypothesis should be tested in a more severe pulmonary complicated group.
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http://dx.doi.org/10.1016/j.intimp.2012.12.023DOI Listing
November 2013

Inhibition of cathepsin S reduces allogeneic T cell priming but not graft-versus-host disease against minor histocompatibility antigens.

Biol Blood Marrow Transplant 2012 Apr 14;18(4):546-56. Epub 2011 Dec 14.

Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Cathepsin (Cathepsin) S, L, and B proteases mediate antigen presentation on major histocompatibility complex (MHC) class II by degrading the invariant chain Ii, which blocks peptide loading. The ability of the Cathepsin S inhibitor LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone phenyl) to impede antigen presentation has led its development as a therapy for autoimmune diseases. There is substantial evidence that donor T cell recognition of host minor histocompatibility antigens (miHA) and subsequent destruction of host tissue mediates graft-versus-host disease (GVHD). We hypothesized that enzymes involved in antigen presentation may play a role in the development of GVHD. Using the C57BL/6 → BALB.B minor mismatch acute GVHD (aGVHD) model, we found that the cathepsin S activity of spleens from allogenetically transplanted mice were significantly increased 1 week after transplantation compared with syngeneic mice. Although LHVS decreased T cell priming responses against both single OVA antigen and miHA in vitro, LHVS did not reduce the severity of aGVHD. In fact, LHVS exacerbated a CD4(+)-T cell-dependent model of GVHD similar to chronic GVHD. This suggests that cytokines rather than T cells may mediate much of the damage in the aGVHD model and that therapeutics based on inhibition of antigen presentation for GVHD must be approached with caution.
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http://dx.doi.org/10.1016/j.bbmt.2011.11.027DOI Listing
April 2012

Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Children's Oncology Group Study ASCT0031.

Biol Blood Marrow Transplant 2011 Dec 25;17(12):1804-13. Epub 2011 May 25.

Children's Oncology Group, Pediatric Hematology/Oncology/Bone Marrow Transplantation, British Columbia Children's Hospital/University of British Columbia, Vancouver, British Columbia, Canada.

Numerous mechanisms underlie chronic graft-versus-host disease (cGVHD), including skewing of Th1/Th2 cytokine expression. There are biological differences between early-onset and late-onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early- or late-onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children's Oncology Group Phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon (IFN)-γ and interleukin (IL)-2, -4, and -10 from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction. Early-onset cGVHD (n = 33) was characterized by decreased expression of IFN-γ and IL-2 mRNA after nonspecific phorbol 12-myristate 13-acetate-ionomycin stimulation. In contrast, late-onset cGVHD (n = 11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti-CD3 stimulation of T cells. Receiver-operating characteristic curve analysis revealed that IFN-γ expression was correlated with the absence of early cGVHD (area under the curve [AUC] = 0.77) and that IL-4 (AUC = 0.89) and IL-2 (AUC = 0.84) expression was correlated with the absence of late cGVHD. There was no correlation between cytokine expression and a specific immune cell subset. Increased expression of Foxp3 mRNA was seen in early-onset cGVHD and late controls. The different time-dependent cytokine profiles in patients with newly diagnosed cGVHD suggests that the mechanisms underlying cGVHD are temporally regulated. Although larger validation studies are needed, our data suggest that cytokine profiles have a potential use as biomarkers for the diagnosis of cGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2011.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3190042PMC
December 2011

Diosgenin modulates vascular smooth muscle cell function by regulating cell viability, migration, and calcium homeostasis.

J Pharmacol Exp Ther 2011 Mar 21;336(3):925-39. Epub 2010 Dec 21.

Child and Family Research Institute, Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada.

In this study, we compared the potencies of diosgenin, a plant-derived sapogenin structurally similar to estrogen and progesterone, on vascular smooth muscle functions ranging from contraction and migration to apoptosis. The effects of diosgenin on vascular smooth muscle cell viability and migration were measured using a primary mouse aortic smooth muscle cell culture. The effects of diosgenin on smooth muscle cell contraction and calcium signaling were investigated in the isolated mouse aorta using wire myography and confocal microscopy, respectively. Here, we report that in cultured cells diosgenin (≥ 25 μM) induces apoptosis as measured by the number of annexin V-positive cells and caspase-3 cleavage, while decreasing cell viability as indicated by protein kinase B/Akt phosphorylation. In addition, diosgenin blocks smooth muscle cell migration in a transwell Boyden chamber in response to serum treatment and response to injury in a cell culture system. Diosgenin (≥ 25 μM) also significantly blocks receptor-mediated calcium signals and smooth muscle contraction in the isolated aorta. There is no difference in the inhibitory effects of diosgenin on vascular smooth muscle contraction between the endothelium-intact and endothelium-denuded aortic segments, indicating that they are caused by altered smooth muscle activity. Our findings suggest that over the concentration range of 10 to 15 μM diosgenin may provide overall beneficial effects on diseased vascular smooth muscle cells by blocking migration and contraction without any significant cytopathic effects, implying a potential therapeutic value for diosgenin in vascular disorders.
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http://dx.doi.org/10.1124/jpet.110.172684DOI Listing
March 2011

DNAs from Brucella strains activate efficiently murine immune system with production of cytokines, reactive oxygen and nitrogen species.

Iran J Allergy Asthma Immunol 2009 Sep;8(3):127-34

Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.

Brucellosis is an infectious disease with high impact on innate immune responses which is induced partly by its DNA. In the present study the potential differences of wild type and patients isolates versus attenuated vaccine strains in terms of cytokines, ROS and NO induction on murine splenocytes and peritoneal macrophages were investigated. This panel varied in base composition and included DNA from B. abortus, B. melitensis, B.abortus strain S19 and melitensis strain Rev1, as attenuated live vaccine. Also we included Escherichia coli DNA, calf thymus DNA (a mammalian DNA), as controls. These DNA were evaluated for their ability to stimulate IL-12, TNF-alpha, IL-10, IFN-gamma and ROS production from spleenocytes as well as NO production from peritoneal macrophages. Spleen cells were cultured in 24 well at a concentration of 106 cells/ ml with subsequent addition of 10 microg/ml of Brucella or Ecoli DNAs. These cultures were incubated at 37 degrees C with 5% CO2 for 5 days. Supernatants were harvested and cytokines, ROS and NOx were evaluated. It was observed that TNF-alpha was induced in days 1,3,5 by all Brucella strains DNAs and E. coli DNA, IL-10 only was induced in day 1, IFN- gamma was induced only in day 5 and IL-12 not induced. ROS and NOx were produced by all strains; however, we observed higher production of NOx which were stimulated by DNA of B. melitensis.
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http://dx.doi.org/08.03/ijaai.127134DOI Listing
September 2009

Leishmania major lipophosphoglycan: discrepancy in Toll-like receptor signaling.

Exp Parasitol 2010 Feb 19;124(2):214-8. Epub 2009 Sep 19.

Institute of Biotechnology, University of Shiraz, Shiraz, Iran.

Lipophosphoglycan (LPG) is structurally characterized by a series of phosphoglycan repeat units. Cellular LPG, isolated from promastigotes, has a very similar structure to culture supernatant LPG, but differs in the average number of phosphorylated oligosaccharide repeat units and in glycan composition. Comparison of these LPGs with capillary electrophoresis and immunoblotting indicate that these molecules are highly conserved structurally and composed of galactosylated Gal-Man repeats but their size and molecular weight are very different which is due to glycan portion. There are 30 and 20 repeat units in sLPG and mLPG, respectively. Both LPGs induced nitric oxide in macrophages cell line while sLPG had the higher stimulatory effect. In the presence of anti-TLR2 nitric oxide stimulated by LPG was reduced to control levels. In addition, in the presence of anti-TLR4, nitric oxide stimulated by LPGs was not affected. We propose that lipophosphoglycan induces nitric oxide production via TLR2 signaling pathway.
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http://dx.doi.org/10.1016/j.exppara.2009.09.017DOI Listing
February 2010

Serum levels of IL-8 and IL-6 in the long term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study.

Int Immunopharmacol 2009 Dec 11;9(13-14):1482-8. Epub 2009 Sep 11.

Department of Internal Medicine, Shahed University, Tehran, Islamic Republic of Iran.

Sulfur mustard (SM) is a blistering chemical agent which has short and long term toxicity against many organs. The respiratory tract is one of the main targets, and is the most disabling long term complication of SM. Inflammatory mediators especially IL-8 and IL-6 play the primary role in the various chronic pulmonary diseases. Sardasht-Iran Cohort Study (SICS) was designed to evaluate immunological and molecular parameters in SM exposed people 20 years after exposure. In the present study, the association of the serum levels of IL-8, IL-6, C reactive protein (CRP) and rheumatoid factor (RF) with long term pulmonary involvement was evaluated. There were 348 exposed and 120 control participants. The clinical evaluations were done for all subjects and Spirometry was performed according to American Thoracic Society Criteria. Severity of pulmonary involvement was assessed by Global Initiative for chronic Obstructive Lung Disease (GOLD) classification. The serum levels of IL-8, IL-6 and RF were assessed by ELISA assay. CRP was assessed by photometric method. The serum levels of IL-8 and IL-6 significantly decreased in the SM exposed participants compared to the control group. There were no significant associations between the serum levels of IL-8 and pulmonary symptoms (chronic cough, sputum, hemoptysis, and dyspnea), pulmonary findings (crackles, rales, and wheezing) as well as spirometry parameters. IL-6 was associated with wheezing and CRP was associated with wheezing and rales in SM exposed group. We concluded the serum levels of these inflammatory mediators probably do not have any major role in pathogenesis and persistence of pulmonary complications and do not reflect the degree of severity of pulmonary involvement following SM exposure.
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http://dx.doi.org/10.1016/j.intimp.2009.09.002DOI Listing
December 2009

Alterations in serum levels of inflammatory cytokines (TNF, IL-1alpha, IL-1beta and IL-1Ra) 20 years after sulfur mustard exposure: Sardasht-Iran cohort study.

Int Immunopharmacol 2009 Dec 11;9(13-14):1466-70. Epub 2009 Sep 11.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Mustard gas, even in low doses, has the ability to inflict damage in multiple organs especially the skin, eyes, as well as the respiratory tract. This damage may cause many complications which persist during the lifespan of exposed subjects. Pro-inflammatory cytokines including TNF, IL-1alpha, IL-1beta and IL-1Ra cause systemic inflammatory reactions and numerous changes including altered cell signaling and migration, changes in cytokine production and fever. The aim of this study was to determine the serum levels of these cytokines in subjects who were exposed to mustard gas 20 years ago in comparison with an unexposed control group. In this historical cohort study 368 sulfur mustard (SM) exposed participants from Sardasht and 126 age-matched unexposed volunteers from Rabat (a nearby town) as controls were chosen by a random systematic sampling. The serum concentrations of IL-1alpha, IL-1beta, IL-1Ra and TNF were measured by a sandwich ELISA technique. Median of the serum levels of cytokines TNF, IL-1alpha, IL-1beta and IL-1Ra in the control group was 23.79, 1.89, 1.91 and 32.9 pg/ml respectively, while in the SM-exposed participants these values were 11.11, 0.81, 1.73 and 26.7 pg/ml respectively. The serum pro-inflammatory cytokine levels were significantly lower in the exposed group than in controls (p<0.01). There was also significant positive correlation between concentration of all of mentioned cytokines, the strongest being between IL-1beta and TNF (r=0.809 in the control group). The observed down-regulation of pro-inflammatory cytokines should be considered in interpretation of diagnosis and therapeutic measures taken to improve clinical complications.
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http://dx.doi.org/10.1016/j.intimp.2009.09.001DOI Listing
December 2009

Alterations in the serum levels of chemokines 20 years after sulfur mustard exposure: Sardasht-Iran Cohort Study.

Int Immunopharmacol 2009 Dec 6;9(13-14):1471-6. Epub 2009 Sep 6.

Immunoregulation Research Center, Shahed University, Tehran, Islamic Republic of Iran.

The serum levels of four important and well characterized inflammatory chemokines including MCP-1/CCL2, RANTES/CCL5, IL-8/CXCL8 and Fractalkine/CX3CL1 were evaluated in sulfur mustard (SM) exposed Iranian population 20 years after exposure. In this historical cohort study 372 SM exposed participants from Sardasht, and 128 unexposed participants as controls were studied. The serum concentrations of chemokines were measured by a sandwich ELISA technique. The serum concentrations in the exposed comparing to the control group were 201.86 vs 180.60 pg/ml (p=0.002), for MCP-1/CCL2, 1182.6 vs 1393.1pg/ml (p=0.021) for RANTES/CCL5, 12.61 vs 15 pg/ml (p=0.002) for IL-8/CXCL8 and 0.696 vs 0.0648 (p=0.413) for Fractalkine/CX3CL1. In conclusion, elevated levels of MCP-1/CCL2 may suggest an anti inflammatory response and decreased levels of IL-8/CXCL8 and RANTES/CCL5 may represent a different pathophysiology and diverse molecular mechanisms involved in long term clinical manifestations of SM exposure. However, further prospect into their role in the pathogenesis of SM remains to be done.
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http://dx.doi.org/10.1016/j.intimp.2009.08.022DOI Listing
December 2009

Serum soluble Fas ligand and nitric oxide in long-term pulmonary complications induced by sulfur mustard: Sardasht-Iran Cohort Study.

Int Immunopharmacol 2009 Dec 4;9(13-14):1489-93. Epub 2009 Sep 4.

Immunoregulation Research Center, Shahed University, Tehran, Iran.

Sulfur mustard (SM) has short- and long-term toxicity against various organs including the respiratory system. However, the basic and molecular mechanisms of SM long-term toxicity have not clearly been defined. Thus, the aim of this study was to evaluate the association of soluble Fas ligand (sFasL) as well as nitric oxide (NO) serum levels with long-term pulmonary complications in a SM exposed population 20 years after SM exposure. In this historical cohort study 372 male SM exposed subjects and 128 age-matched unexposed controls were studied. Clinical evaluation and pulmonary function tests were carried out for all participants and serum concentrations of sFasL and NO measured. According to our results, the serum levels of sFasL and NO were not significantly different between the exposed and control groups. However, the serum levels of sFasL in the exposed group with pulmonary problems were significantly higher than their corresponding in the control group (116.711+/-81.166 vs 86.027+/-30.199 and p=0.028). Furthermore a significant elevation in sFasL levels was found in the exposed subjects with pulmonary problems compared to those exposed participants without pulmonary problems (116.711+/-81.166 vs 90.692+/-57.853 and p=0.004). Based on Global Initiative for chronic Obstructive Lung Disease (GOLD) classification analysis a positive correlation was observed between sFasL levels and pulmonary problems. There was also a significant negative correlation between sFasL and the white blood cell (WBC) count in the SM exposed cohort, but not in the control group. No significant association was shown between NO and pulmonary impairment in the SM exposed subjects. Thus, our results indicate that elevated serum levels of sFasL may be associated with progression of pulmonary diseases in the SM exposed subjects.
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http://dx.doi.org/10.1016/j.intimp.2009.08.019DOI Listing
December 2009

Comparison of QuantiFERON TB-G-test to TST for detecting latent tuberculosis infection in a high-incidence area containing BCG-vaccinated population.

J Eval Clin Pract 2009 Feb;15(1):148-51

Immunology Department Pasteur Institute of Iran, Tehran, Iran.

Objective: Until recently, the only tool for detection of latent tuberculosis infection (LTBI) was the tuberculin skin test (TST). QuantiFERON-TB Gold In-Tube test (QFT) is a promising in vitro diagnostic test for LTBI that has potential advantages over the TST. In this study we aimed to compare QFT with TST for diagnosis of LTBI.

Patients And Methods: A total of 186 BCG-vaccinated subjects enrolled in study. They underwent TST and QFT assay. They divided in two groups. Group 1 includes individuals who were at low risk for exposure to M. tuberculosis (LRG) and Group 2 includes individuals who were likely to have been exposed to M. tuberculosis infections (HRG).

Results: Overall agreement between QFT and TST was 89.3% (kappa = 0.052). In LRG, agreement between the two tests was 52.6% (95% confidence interval, 44-60%) with kappa-values of 0.019. In HRG agreement between the two tests was 63.2% (95% confidence interval, 42-84%) with kappa-values of 0.28.

Conclusion: In conclusion, the QFT assay showed acceptable results for determining latent M. tuberculosis infection in vaccinated population. The decision to select QFT over TST will depend on the population, purpose of testing and resource availability.
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http://dx.doi.org/10.1111/j.1365-2753.2008.00970.xDOI Listing
February 2009