Systemic IL-15, IFN-γ and IP-10/CXCL10 Signature Associated with Effective Immune Response to SARS-CoV-2 in BNT162b2 mRNA Vaccine Recipients

Decitabine is an approved hypomethylating agent used for treating hematological malignancies. Although decitabine targets altered cells, epidrugs can trigger immunomodulatory effects, reinforcing the hypothesis of immunoregulation in treated patients. We therefore aimed to evaluate the impact of decitabine treatment on the phenotype and functions of monocytes and macrophages, which are pivotal cells of the innate immunity system. In vitro decitabine administration increased bacterial phagocytosis and IL-8 release, but impaired microbicidal activity of monocytes. In addition, during monocyte-to-macrophage differentiation, treatment promoted the M2-like profile, with increased expression of CD206 and ALOX15. Macrophages also demonstrated reduced infection control when exposed to Mycobacterium tuberculosis in vitro. However, cytokine production remained unchanged, indicating an atypical M2 macrophage. Furthermore, when macrophages were cocultured with lymphocytes, decitabine induced a reduction in the release of inflammatory cytokines such as IL-1β, TNF-α, and IFN-γ, maintaining IL-10 production, suggesting that decitabine could potentialize M2 polarization and might be considered as a therapeutic against the exacerbated immune response.

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Sarcoma IL-12 overexpression facilitates NK cell immunomodulation

Scientific Reports ◽

10.1038/s41598-021-87700-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mary Jo Rademacher ◽

Anahi Cruz ◽

Mary Faber ◽

Robyn A. A. Oldham ◽

Dandan Wang ◽

...

Keyword(s):

Immune Response ◽

Cell Lines ◽

Nk Cell ◽

Autologous Tumor ◽

Murine Models ◽

Lentiviral Transduction ◽

Ifn Γ ◽

Human Sarcoma

AbstractInterleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.

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Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002269 ◽

2021 ◽

Vol 9 (6) ◽

pp. e002269

Author(s):

Shota Aoyama ◽

Ryosuke Nakagawa ◽

Satoshi Nemoto ◽

Patricio Perez-Villarroel ◽

James J Mulé ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Tumor Growth ◽

Ex Vivo ◽

T Cell Response ◽

Effector Function ◽

Checkpoint Blockade ◽

Necrosis Factor Alpha ◽

Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

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A Summary of the Third Global Interferon-γ Release Assay Symposium

Infection Control and Hospital Epidemiology ◽

10.1086/670634 ◽

2013 ◽

Vol 34 (6) ◽

pp. 619-624 ◽

Cited By ~ 2

Author(s):

Antonino Catanzaro ◽

Charles Daley

Keyword(s):

Immune Response ◽

Tuberculin Skin Test ◽

Skin Test ◽

Interferon Γ ◽

Enzyme Linked Immunosorbent Assay ◽

In Vitro Tests ◽

The Third ◽

Specific Antigens ◽

Ifn Γ

Studies over the past several decades have dramatically increased our understanding of the immune response to Mycobacterium tuberculosis infection, and advances in proteomics and genomics have led to a new class of immune-diagnostic tests, termed interferon-γ (IFN-γ) release assays (IGRAs), which appear to obviate many of the problems encountered with the tuberculin skin test (TST). Worldwide, 2 IGRAs are currently commercially available. QuantiFERON-TB Gold In-Tube (Cellestis) is a third-generation product that uses an enzyme-linked immunosorbent assay to measure IFN-γ generated in whole blood stimulated with M. tuberculosis–specific antigens. T-Spot-TB (Oxford Immunotec) employs enzyme-linked immunosorbent spot technology to enumerate the number of purified lymphocytes that respond to M. tuberculosis–specific antigens by producing IFN-γ. These in vitro tests measure the host immune response to M. tuberculosis–specific antigens, which virtually eliminates false-positive cross reactions caused by bacillus Calmette-Guérin vaccination and/or exposure to environmental nontuberculous mycobacteria that plague the interpretation and accuracy of the tuberculin skin test (TST). The high specificity of IGRAs, together with sensitivity commensurate with or better than that of the TST, promises an accurate diagnosis and the ability to focus tuberculosis-control activities on those who are actually infected with M. tuberculosis. The Third Global Symposium was held over a 3-day period and was presented by the University of California, San Diego, Continuing Medical Education department; slides and sound recordings of each presentation are available at http://cme.ucsd.edu/igras/syllabus.html. A moderated discussion is also available at http://cme.ucsd.edu/igrasvideo. This document provides a summary of the key findings of the meeting, specifically focusing on the use of IGRAs in screening healthcare worker populations.

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Hepatic DR5 Induces Apoptosis and Limits Adenovirus Gene Therapy Product Expression in the Liver

Journal of Virology ◽

10.1128/jvi.76.11.5692-5700.2002 ◽

2002 ◽

Vol 76 (11) ◽

pp. 5692-5700 ◽

Cited By ~ 28

Author(s):

Huang-Ge Zhang ◽

Jinfu Xie ◽

Liang Xu ◽

Pingar Yang ◽

Xin Xu ◽

...

Keyword(s):

Gene Therapy ◽

Immune Response ◽

Transgene Expression ◽

Cell Activation ◽

Nk Cell ◽

Death Domain ◽

Activated T Cells ◽

Tnf Α ◽

Product Expression ◽

Ifn Γ

ABSTRACT A major limitation of adenovirus (Ad) gene therapy product expression in the liver is subsequent elimination of the hepatocytes expressing the gene therapy product. This elimination is caused by both necrosis and apoptosis related to the innate and cell-mediated immune response to the Ad. Apoptosis of hepatocytes can be induced by the innate immune response by signaling through death domain receptors on hepatocytes including the tumor necrosis factor alpha (TNF-α) receptor (TNFR), Fas, and death domain receptors DR4 and DR5. We have previously shown that blocking signaling through TNFR enhances and prolongs gene therapy product expression in the liver. In the present study, we constructed an Ad that produces a soluble DR5-Fc (AdsDR5), which is capable of neutralizing TNF-related apoptosis-inducing ligand (TRAIL). AdsDR5 prevents TRAIL-mediated apoptosis of CD3-activated T cells and decreases hepatocyte apoptosis after AdCMVLacZ administration and enhances the level and duration of lacZ transgene expression in the liver. In addition to blocking TRAIL and directly inhibiting apoptosis, AdsDR5 decreases production of gamma interferon (IFN-γ) and TNF-α and decreases NK cell activation, all of which limit Ad-mediated transgene expression in the liver. These results indicate that (i) AdsDR5 produces a DR5-Fc capable of neutralizing TRAIL, (ii) AdsDR5 can reduce activation of NK cells and reduce induction of IFN-γ and TNF-α after Ad administration, and (iii) administration of AdsDR5 can enhance Ad gene therapy in the liver.

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Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

Cancers ◽

10.3390/cancers13010019 ◽

2020 ◽

Vol 13 (1) ◽

pp. 19

Author(s):

Roxanne Wouters ◽

Sien Bevers ◽

Matteo Riva ◽

Frederik De Smet ◽

An Coosemans

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Mouse Models ◽

Standard Of Care ◽

Preclinical Studies ◽

Success Rates ◽

Immunocompetent Mouse ◽

Full Spectrum ◽

Effective Immune Response ◽

Radio Chemotherapy

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.

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Heavy metal intoxication compromises the host cytokine response in Ascaris Suum model infection

Helminthologia ◽

10.1515/helmin-2015-0063 ◽

2016 ◽

Vol 53 (1) ◽

pp. 14-23 ◽

Cited By ~ 2

Author(s):

E. Dvorožňáková ◽

M. Dvorožňáková ◽

J. Šoltys

Keyword(s):

Heavy Metal ◽

Immune Response ◽

Ascaris Suum ◽

Cytokine Response ◽

Parasitic Infections ◽

Tnf Α ◽

Ifn Γ ◽

High Level ◽

Larval Burden ◽

Heavy Metal Intoxication

SummaryLead (Pb), Cadmium (Cd) and Mercury (Hg) are recognized for their deleterious effect on the environment and immunity where subsequently compromised immune response affects the susceptibility to the potential parasitic infections. This study examined the host cytokine response after heavy metal intoxication (Pb, Cd, and Hg) and subsequent Ascaris suum infection in BALB/c mice. Pb modulated murine immune response towards the Th2 type of response (delineated by IL-5 and IL-10 cytokine production) what was also dominant for the outcome of A. suum infection. Chronic intoxication with Pb caused a more intensive development of the parasite infection. Cd stimulated the Th1 immune response what was associated with increase in IFN-γ production and reduction of larvae present in the liver of intoxicated mice. The larval burden was also low in mice intoxicated with Hg. This was probably not related to the biased Th1/Th2 type of immune response, but rather to the bad host conditions caused by mercury toxicity and high level of pro-cachectic cytokine TNF-α.

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The use of antiviral drug based on technologically processed antibodies to interferon-γ, CD4 receptor and histamine in the treatment of influenza in adults: results of a multicenter open-label randomized comparative trial with oseltamivir

Infekcionnye bolezni ◽

10.20953/1729-9225-2021-1-39-57 ◽

2021 ◽

Vol 19 (1) ◽

pp. 39-57

Author(s):

K.V. Zhdanov ◽

◽

R.F. Khamitov ◽

V.V. Rafalsky ◽

M.P. Mikhaylusova ◽

...

Keyword(s):

Immune Response ◽

B Cell ◽

Open Label ◽

Virus Elimination ◽

Antiviral Immune Response ◽

Cd4 Receptor ◽

Antiviral Efficacy ◽

Ifn Γ ◽

Group 2 ◽

Group 1

Objective. A multicenter open-label randomized controlled clinical trial was aimed to compare the efficacy of the study drug (SD) containing technologically processed affinity purified antibodies (high dilutions) to IFN-γ, CD4 receptor and histamine (Ergoferon) with oseltamivir, and evaluate the influence of SD on the antiviral immune response in adults with seasonal influenza. Patients and methods. 184 outpatients aged 18–70 with confirmed influenza of mild/moderate severity were included and randomized into 2 groups (in a 1:1 ratio). Patients received SD (Group 1, n = 92) or oseltamivir (Group 2, n = 92), according to the instructions for medical use for 5 days. As the primary endpoint, the percentage of patients with recovery/improvement was assessed (according to the data of the patient's diary on days 2–7 and according to the clinical examination on days 3 and 7). Additionally, the duration and severity of influenza symptoms, the percentage of patients with virus elimination (according to RT-PCR of nasopharyngeal samples), the percentage of patients with complications, the percentage of patients prescribed antipyretic drugs, the change in concentration of T cell (IL-2, IL-18, IFN-γ) and B cell antigen-specific (IL-4, IL-16) immune response regulators in serum, the leukocyte phenotypes on days 1, 3 and 7 were evaluated. Statistical analysis was performed using a “Non-Inferiority” design (or no less efficiency/safety). Intention-to-Treat (ITT) analysis data are presented. Results. According to patients’ self-assessment, 53.3% of patients in Group 1 recovered/improved on the 6th day in the morning and 65.2% – in the evening (vs. 53.3% and 57.6% in Group 2, respectively). There were 73.9% recovered/ improved patients on the 7th day in the morning (vs. 67.4% in Group 2). A generalized analysis showed that the treatment results in both groups were comparable (p < 0.0001). According to objective medical examination, 79.3% of patients in the SD group and 74.0% of patients in the Оseltamivir group recovered/improved on the 7th day (p < 0.0001). The antiviral efficacy of SD was not inferior to oseltamivir, which was confirmed by comparable periods of virus elimination, duration and severity of fever and other influenza symptoms. A moderate activating effect of SD on the immune system was evaluated. A significant, compared to oseltamivir, increase in the concentration of IL-2 and IL-4 on the 3rd day of treatment (p = 0.03 and p = 0.04 vs. the oseltamivir group), and IFN-γ on the 3rd and the 7th days (p = 0.012 and p < 0.0001, respectively, vs. the oseltamivir group). No stimulating effect of SD on the growth and differentiation of immune cells was found. Conclusion. SD is effective and safe in the treatment of patients with influenza. The therapeutic and antiviral efficacy of SD is comparable to that of oseltamivir. The antiviral activity of SD affects the interferon system and the concentration of the cytokines IL-2 and IL-4, regulators of the T and B cell immune response. At the same time, there is no significant stimulation of interferon production with further development of hyporeactivity. Key words: influenza, oseltamivir, therapy, cytokines, Еrgoferon

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Cytokine expression in the duodenal mucosa of patients with visceral leishmaniasis

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822010000400011 ◽

2010 ◽

Vol 43 (4) ◽

pp. 393-395 ◽

Cited By ~ 4

Author(s):

Kleber Giovanni Luz ◽

Felipe Francisco Tuon ◽

Maria Irma Seixas Duarte ◽

Guilherme Mariz Maia ◽

Paulo Matos ◽

...

Keyword(s):

Immune Response ◽

Gastrointestinal Tract ◽

Visceral Leishmaniasis ◽

Intestinal Bacteria ◽

Duodenal Mucosa ◽

Control Group ◽

Tnf Α ◽

Organ Specific ◽

Ifn Γ

INTRODUCTION: Visceral leishmaniasis (VL) is a neglected tropical disease with a complex immune response in different organs. This pattern of organ-specific immune response has never been evaluated in the gastrointestinal tract. The aim of this study was to determine the in situ immune response in duodenal biopsies on patients with VL. METHODS: A case-control study was conducted on 13 patients with VL in comparison with nine controls. The immune response was evaluated using immunohistochemistry, for CD4, CD8, CD68, IL-4, IFN-γ, TNF-α and IL-10. Histological findings from the villi, crypts and inflammatory process were analyzed. RESULTS: All the cases of VL presented Leishmania antigens. No antigen was detected in the control group. The villus size was greater in the VL patients (p < 0.05). CD68 (macrophages) and CD4 levels were higher in the VL patients (p < 0.05). No differences in the expression of CD8, TNF-α, IL-10 or IL-4 were demonstrated. The number of cells expressing IFN-γ was lower in the VL patients (p < 0.05). CONCLUSIONS: Low levels of cytokines were found in the gastrointestinal tract of patients with VL. This pattern was not found in other organs affected by the disease. Immunotolerance of this tissue against Leishmania could explain these findings, as occurs with intestinal bacteria.

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