scholarly journals Inhibition of acute leukemia with attenuated Salmonella typhimurium strain VNP20009

2020 ◽  
Author(s):  
Meirong Li ◽  
Mengmeng Lu ◽  
Yunhao Lai ◽  
Xindan Zhang ◽  
Yuyu Li ◽  
...  
Keyword(s):  
Blood Cell ◽  
Acute Leukemia ◽  
Salmonella Typhimurium ◽  
Immune Cells ◽  
Caspase 3 ◽  
Fluorescent Protein ◽  
Solid Cancer ◽  
Ki 67 ◽  
Attenuated Salmonella Typhimurium ◽  
Ifn Γ

Abstract Background Despite recent promising progress, the prognosis of acute leukemia (AL) patients remains to be improved. New therapies are therefore still needed. Spontaneous complete remission (SCR) of leukemia caused by severe bacterial infection in clinic suggests the possibility of bacterial treatment for AL. An engineered attenuated Salmonella typhimurium VNP20009 with good tolerance and safety has been shown to be highly effective as an anti-tumor agent in many solid cancer models, but it has not been applied in leukemia. Therefore, we selected VNP20009 as a candidate for the bacterial therapy of AL in this study. Methods Murine xenograft tumor models were used to verify the growth inhibition effect of VNP20009 on AL tumors. Histopathological features of the tumor were observed by H&E staining, Ki-67 immunohistochemical staining and TUNEL immunofluorescence staining. The apoptosis proteins Bax and cleaved caspase-3 in tumors were detected by Western blotting. The ratios of apoptosis, green fluorescent protein positive (GFP + ) cells and immune cells were detected by flow cytometry. Blood cell count were counted by IDEXX automatic five-classification blood cell analyzer. Detection of cytokines and chemokines in serum was completed on a Luminex Multi-factor Detection Platform. Results VNP20009 can induce apoptosis of AL cells by up-regulating the expression levels of Bax and cleaved caspase-3 . Furthermore, VNP20009 significantly inhibited the proliferation of MLL-AF9-induced AML cells and prolonged the survival of the AML-carrying mice. VNP20009 restored the counts of white blood cell and its five subsets in PB to near-physiological values, and elevated the levels of certain cytokines, such as tumor necrosis factor-α (TNF-α), leukemia inhibitory factor (LIF), interferon-γ (IFN-γ), chemokine C-X-C motif ligand-10 (CCXC-10) and C-C motif ligand-2 (CCL-2). Moreover, the ratio of immune cells, including natural killer cells (NKs), CD4 + Th1-type cells and CD8 + IFN-γ-producing effector T cells were highly upregulated in the AML mice treated with VNP20009. Conclusions VNP20009 induces the apoptosis of AL cells and activates the immune system, leading to the development of a strong and effective anti-tumor systemic response and tumor remission in acute leukemia. Keywords: acute leukemia, attenuated Salmonella typhimurium VNP20009, immunotherapy, bacterial cancer therapy, apoptosis

scholarly journals Induction of Effective Immunity against Trypanosoma cruzi

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Tere Williams ◽  
Ignacio Guerrero-Ros ◽  
Yanfen Ma ◽  
Fabiane Matos dos Santos ◽  
Philipp E. Scherer ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Immune Cells ◽  
Fluorescent Protein ◽  
Rapid Expansion ◽  
Public Health Issue ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Ifn Γ ◽  
Green Fluorescent

ABSTRACT Chagas disease, caused by Trypanosoma cruzi, is a major public health issue. Limitations in immune responses to natural T. cruzi infection usually result in parasite persistence with significant complications. A safe, effective, and reliable vaccine would reduce the threat of T. cruzi infections; however, no suitable vaccine is currently available due to a lack of understanding of the requirements for induction of fully protective immunity. We established a T. cruzi strain expressing green fluorescent protein (GFP) under the control of dihydrofolate reductase degradation domain (DDD) with a hemagglutinin (HA) tag, GFP-DDDHA, which was induced by trimethoprim-lactate (TMP-lactate), which results in the death of intracellular parasites. This attenuated strain induces very strong protection against reinfection. Using this GFP-DDDHA strain, we investigated the mechanisms underlying the protective immune response in mice. Immunization with this strain led to a response that included high levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), as well as a rapid expansion of effector and memory T cells in the spleen. More CD8+ T cells differentiate to memory cells following GFP-DDDHA infection than after infection with a wild-type (WT) strain. The GFP-DDDHA strain also provides cross-protection against another T. cruzi isolate. IFN-γ is important in mediating the protection, as IFN-γ knockout (KO) mice failed to acquire protection when infected with the GFP-DDDHA strain. Immune cells demonstrated earlier and stronger protective responses in immunized mice after reinfection with T. cruzi than those in naive mice. Adoptive transfers with several types of immune cells or with serum revealed that several branches of the immune system mediated protection. A combination of serum and natural killer cells provided the most effective protection against infection in these transfer experiments.

Effect of salmonella typhimurium A1-R on quiescent cancer cells that do not respond to standard chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13576-e13576
Author(s):  
Shuya Yano ◽  
Yong Zhang ◽  
Fuminari Uehara ◽  
Yukihiko Hiroshima ◽  
Shinji Miwa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Salmonella Typhimurium ◽  
Cancer Cells ◽  
Nude Mice ◽  
Fluorescent Protein ◽  
Confocal Imaging ◽  
Cytotoxic Agents ◽  
Cycle Phase ◽  
Solid Cancer ◽  
Proliferating Cells

e13576 Background: Quiescent cancer cells are a major impediment to treating solid cancer with chemotherapy, since in most tumors the majority of the cells are quiescent. Methods: The cell-cycle phase of each human MKN45 gastric cancer cell was imaged using a fluorescence ubiquitination cell cycle indicator (FUCCI). With FUCCI, quiescent cancer cells express mKusabira-Orange fluorescent protein (red) and proliferating cells express mAzami-Green fluorescent protein (green). FUCCI-labeled cancer cells in tumor spheres and subcutaneous tumor in nude mice were treated with Salmonella typhimurium A1-R. Results: Time-lapse confocal imaging showed that cancer cells in tumor spheres in serum-free culture become and remained quiescent. S. typhimurium A1-R infected and killed quiescent cancer cells in tumor spheres. In contrast, cytotoxic agents did not kill the quiescent cancer cells in the tumor spheres. S. typhimurium A1-R targeting of FUCCI-expressing subcutaneous tumors growing in nude mice resulted in the killing of quiescent cancer cells resistant to cytotoxic agents. Conclusions: S. typhimurium A1-R can kill quiescent cancer cells which suggests a new therapeutic paradigm potentially more effective than current therapeutics which are ineffective against quiescent cancer cells.

scholarly journals Salmonella typhimurium Infection in Mice Induces Nitric Oxide-Mediated Immunosuppression through a Natural Killer Cell-Dependent Pathway

1998 ◽  
Vol 66 (12) ◽  
pp. 5862-5866 ◽  
Author(s):  
Martin G. Schwacha ◽  
Joseph J. Meissler ◽  
Toby K. Eisenstein
Keyword(s):  
Nitric Oxide ◽  
Salmonella Typhimurium ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nitric Oxide Production ◽  
Oxide Production ◽  
Ifn Γ

ABSTRACT Splenocytes isolated from C57BL/6J female mice 3 to 7 days after inoculation with an attenuated strain of Salmonella typhimurium produced high levels of nitric oxide (39 to 77 μM) and gamma interferon (IFN-γ). Additionally, spleen cell cultures fromSalmonella-inoculated mice were markedly suppressed in their ability to generate an in vitro plaque-forming cell (PFC) response to sheep erythrocytes. Depletion of natural killer (NK) cells from the immune splenocyte population markedly reduced nitric oxide production, prevented suppression of PFC responses, and completely abrogated IFN-γ release. Treatment of NK cell-depleted immune cells with IFN-γ restored nitric oxide production to levels comparable to those of intact immune cells and also restored the immunosuppression. These results suggest that NK cells regulate the induction of nitric oxide-mediated immunosuppression following infection with S. typhimurium through the production of IFN-γ.

scholarly journals Inhibition of acute leukemia with attenuated Salmonella typhimurium strain VNP20009

2020 ◽  
Vol 129 ◽  
pp. 110425
Author(s):  
Meirong Li ◽  
Mengmeng Lu ◽  
Yunhao Lai ◽  
Xindan Zhang ◽  
Yuyu Li ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Salmonella Typhimurium ◽  
Typhimurium Strain ◽  
Attenuated Salmonella Typhimurium

Development and study of a method for cell separation during white blood cell segmentation on images of bone marrow preparations in information and measurement systems for diagnostics of acute leukemia

2020 ◽  
pp. 68-72
Author(s):  
V.G. Nikitaev ◽  
A.N. Pronichev ◽  
V.V. Dmitrieva ◽  
E.V. Polyakov ◽  
A.D. Samsonova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blood Cell ◽  
Acute Leukemia ◽  
White Blood Cell ◽  
Cell Separation ◽  
Large Scale ◽  
Bone Marrow Cells ◽  
Automated Analysis ◽  
Cell Segmentation ◽  
Measurement Systems

The issues of using of information and measurement systems based on processing of digital images of microscopic preparations for solving large-scale tasks of automating the diagnosis of acute leukemia are considered. The high density of leukocyte cells in the preparation (hypercellularity) is a feature of microscopic images of bone marrow preparations. It causes the proximity of cells to eachother and their contact with the formation of conglomerates. Measuring of the characteristics of bone marrow cells in such conditions leads to unacceptable errors (more than 50%). The work is devoted to segmentation of contiguous cells in images of bone marrow preparations. A method of cell separation during white blood cell segmentation on images of bone marrow preparations under conditions of hypercellularity of the preparation has been developed. The peculiarity of the proposed method is the use of an approach to segmentation of cell images based on the watershed method with markers. Key stages of the method: the formation of initial markers and builds the lines of watershed, a threshold binarization, shading inside the outline. The parameters of the separation of contiguous cells are determined. The experiment confirmed the effectiveness of the proposed method. The relative segmentation error was 5 %. The use of the proposed method in information and measurement systems of computer microscopy for automated analysis of bone marrow preparations will help to improve the accuracy of diagnosis of acute leukemia.

scholarly journals Protective effect of Toxocara vitulorum extract against alpha-naphthylisothiocyanate-induced cholangitis in rat

2020 ◽  
Vol 81 (1) ◽  
Author(s):  
Abeer Mahmoud Badr ◽  
Mohamed Farid ◽  
Ahmed Abdel Aziz Biomy ◽  
Ayman Saber Mohamed ◽  
Noha Ahmed Mahana ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Wistar Rat ◽  
Liver Function Tests ◽  
T Helper ◽  
Standard Drug ◽  
Toxocara Vitulorum ◽  
Stress Markers ◽  
Tnf Α ◽  
Ifn Γ ◽  
Antioxidant Markers

Abstract Background Cholestasis is the major cause of bile acid accumulation leading to liver damage. Chronic infection of worms can modulate the immune response towards T helper (Th)2-related cytokines. The present study aims to evaluate the protective impact of an ascarid nematode Toxocara vitulorum extract (TvE) against alpha-naphthylisothiocyanate (ANIT)-induced cholangitis male wistar rat model compared to ursodeoxycholic acid (UDCA) as a standard drug. Results Pretreatment with TvE and/or UDCA induced a marked reduction in the levels of liver function tests and malondialdehyde, while antioxidant markers were increased compared to cholestatic rats. Pretreatment with either TvE or combination before cholangitis induction attenuated the predominant Th1-related cytokines (IFN-γ and TNF-α) to Th2 (IL-13 and IL-10). TvE administration promoted higher expression levels of Bcl-2 protein and lower levels of caspase-3 compared to cholestatic rats. Conclusions Treatment with TvE has improved the liver functions and elevated the levels of oxidative stress markers. The upregulation of Th2-related cytokines and suppression of apoptosis through caspase-3 might be considered as a potential mechanism of TvE. Thereby, this natural extract revealed an opportunity for use in treatment of cholangitis disease.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

Antitumor effects of Auraptene in 4T1 tumor‐bearing Balb/c mice

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Mohammad Reza. Shiran ◽  
Davar Amani ◽  
Abolghasem Ajami ◽  
Mahshad Jalalpourroodsari ◽  
Maghsoud Khalizadeh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Weight ◽  
Tumor Volume ◽  
Serum Levels ◽  
Ki 67 ◽  
Tumor Bearing ◽  
Paraffin Oil ◽  
Anti Cancer ◽  
Before And After ◽  
Ifn Γ

Abstract Objectives Breast cancer is a common malignant tumor in women with limited treatment options and multiple side effects. Today, the anti-cancer properties of natural compounds have attracted widespread attention from researchers worldwide. Methods In this study, we treated 4T1 tumor-bearing Balb/c mice with intraperitoneal injection of Auraptene, paraffin oil, and saline as two control groups. Body weight and tumor volume were measured before and after treatment. Hematoxylin and eosin (H & E) staining and immunohistochemistry of Ki-67 were used as markers of proliferation. In addition, ELISA assays were performed to assess serum IFN-γ and IL-4 levels. Results There was no significant change in body weight in all animal groups before and after treatment. 10 days after the last treatment, Auraptene showed its anti-cancer effect, which was confirmed by the smaller tumor volume and H & E staining. In addition, Ki-67 expression levels were significantly reduced in tumor samples from the Auraptene-treated group compared to the paraffin oil and saline-treated groups. In addition, in tumor-bearing and normal mice receiving Auraptene treatment, IL-4 serum production levels were reduced, while serum levels of IFN-γ were significantly up-regulated in tumor-bearing mice after Auraptene treatment. Conclusions In the case of inhibition of tumor volume and Ki-67 proliferation markers, Auraptene can effectively inhibit tumor growth in breast cancer animal models. In addition, it might increases Th1 and CD8 + T cell responses after reducing IL-4 serum levels and IFN-γ upregulation, respectively. However, further research is needed to clarify its mechanism of action.

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