Dose-Dependent Enhancements by Interferon-γ on Functional Responses of Neutrophils From Chronic Granulomatous Disease Patients

Abstract Interferon-γ (IFN-γ) is recommended as prophylaxis against infections in patients with chronic granulomatous disease (CGD). However, since the optimal dose, the dosing interval, and the mechanisms of action are not well-defined, we studied the effects on CGD neutrophil (PMN) functions ex vivo of interferon-γ (IFN-γ). Evaluations were made on oxidative capacity, measured by superoxide anion production and chemiluminescence after stimulation with f-met-leu-phe (f-MLP) or phorbol-myristate-acetate, the killing of Aspergillus fumigatus hyphae (assessed as conversion of the tetrazolium salt MTT to formazan), and on the expression of FcγRI receptor (CD64). After randomization, 9 CGD patients (4 with gp91phox, 3 with p47phox, 1 with p67phox deficiency and 1 with unspecified CGD) were given IFN-γ, either 50 or 100 μg/m2 subcutaneously on 2 consecutive days after double blinded randomization. Furthermore, one female hyperlyonized X-linked carrier with a CGD phenotype was also studied separately after IFN-γ treatment. Evaluations were made the day before and on days 1, 3, 8, and 18 after IFN-γ administration. The killing of A fumigatus hyphae, being close to zero before IFN-γ, was enhanced on day 3, being 36% higher than pretreatment values in the high-dose CGD group and 17% in the low-dose group. The expression of FcγRI on PMN increased 3.7-fold in the high-dose and 2.3-fold in the low-dose CGD group, being maximal on day 1. Oxidative functions were raised in only selected patients represented by different subtypes of CGD. The hyperlyonized carrier of X-linked CGD responded to IFN-γ with more enhanced oxidative responses and Aspergillus killing of her PMNs than the other patients. This study suggests that a higher dose of IFN-γ than currently recommended confers transient enhancements of certain PMN functions in CGD patients.

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Influence of BCG dose and age of inoculated mice on immunoprotection against tuberculosis and expression of IFN-γ/IL-4

Chinese Journal of Agricultural Biotechnology ◽

10.1017/s147923620999026x ◽

2009 ◽

Vol 6 (2) ◽

pp. 171-176

Author(s):

Guo Hui-Jun ◽

Li Bao-Quan ◽

Chai Jia-Qian ◽

Chang Wei-Shan ◽

Wang Chun-Yang ◽

...

Keyword(s):

Low Dose ◽

Interferon Γ ◽

Interleukin 4 ◽

High Dose ◽

Bacille Calmette Guerin ◽

Il Interleukin ◽

Cell Immunity ◽

Ifn Γ ◽

Old Mice

AbstractBalB/C neonate mice and adult BalB/C mice were vaccinated using BCG (Bacille Calmette–Guerin). The pathogenic growth characteristics of BCG in in vitro culture on spleen cells (SPC) were observed and changes in induced expression of IFN (interferon)-γ and IL (interleukin)-4 in SPC were detected using the ELISPOT assay. The results showed that a low dose of BCG (2×103 cfu) exerted 100% immunoprotection on 7-day-old neonate mice and a high dose of BCG (4×104 cfu) exerted 75% immunoprotection. A low dose of BCG (2×103 cfu) exerted 67% immunoprotection on 35-day-old mice. It is also shown that Th1-type cell immunity dominated by IFN-γ was enhanced significantly in the neonate mice injected with a low dose of BCG (2×103 cfu), and Th2-type cell immunity dominated by IL-4 was depressed at the same time. IFN-γ and IL-4 induced by a high dosage of BCG (4×104 cfu) in neonate mice were both increased. IFN-γ and IL-4 induced by a low dose of BCG (2×103 cfu) in 35-day-old mice were also increased. The results indicate that there exists a marked correlation between immunoprotection by BCG in mice and both the immunizing dose and age of the immune animals, which might be relevant to the changes induced by BCG on Th1- and Th2-type cell immunity.

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Persistence of Protective Immunity to Malaria Induced by DNA Priming and Poxvirus Boosting: Characterization of Effector and Memory CD8+-T-Cell Populations

Infection and Immunity ◽

10.1128/iai.70.7.3493-3499.2002 ◽

2002 ◽

Vol 70 (7) ◽

pp. 3493-3499 ◽

Cited By ~ 31

Author(s):

Martha Sedegah ◽

Gary T. Brice ◽

William O. Rogers ◽

Denise L. Doolan ◽

Yupin Charoenvit ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Population ◽

Low Dose ◽

Ex Vivo ◽

Plasmodium Yoelii ◽

Cytolytic Activity ◽

High Dose ◽

Specific Cell ◽

Ifn Γ

ABSTRACT The persistence of immunity to malaria induced in mice by a heterologous DNA priming and poxvirus boosting regimen was characterized. Mice were immunized by priming with DNA vaccine plasmids encoding the Plasmodium yoelii circumsporozoite protein (PyCSP) and murine granulocyte-macrophage colony-stimulating factor and boosting with recombinant vaccinia encoding PyCSP. BALB/c mice immunized with either high-dose (100 μg of p PyCSP plus 30 μg of pGM-CSF) or low-dose (1 μg of p PyCSP plus 1 μg of pGM-CSF DNA) priming were protected against challenge with 50 P. yoelii sporozoites. Protection 2 weeks after immunization was 70 to 100%, persisted at this level for at least 20 weeks, and declined to 30 to 40% by 28 weeks. Eight of eight mice protected at 20 weeks were still protected when rechallenged at 40 weeks. The antigen (Ag)-specific effector CD8+-T-cell population present 2 weeks after boosting had ex vivo Ag-specific cytolytic activity, expressed both gamma interferon (IFN-γ) and tumor necrosis factor alpha, and constituted 12 to 20% of splenic CD8+ T cells. In contrast, the memory CD8+-Ag-specific-cell population at 28 weeks lacked cytolytic activity and constituted only 6% of splenic CD8+ T cells, but at the single-cell level it produced significantly higher levels of IFN-γ than the effectors. High levels of Ag- or parasite-specific antibodies present 2 weeks after boosting had declined three- to sevenfold by 28 weeks. Low-dose priming was similarly immunogenic and as protective as high-dose priming against a 50-, but not a 250-, sporozoite challenge. These results demonstrate that a heterologous priming and boosting vaccination can provide lasting protection against malaria in this model system.

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Benefit/Risk Profile of Combined Antiplatelet Therapy with Ticlopidine and Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648180 ◽

1991 ◽

Vol 65 (05) ◽

pp. 504-510 ◽

Cited By ~ 20

Author(s):

Raffaele De Caterina ◽

Rosa Sicari ◽

Walter Bernini ◽

Guido Lazzerini ◽

Giuliana Buti Strata ◽

...

Keyword(s):

Platelet Function ◽

Low Dose ◽

Bleeding Time ◽

Ex Vivo ◽

Stable Coronary Artery Disease ◽

High Dose ◽

Single Drug ◽

Before And After ◽

Serum Thromboxane ◽

Artery Disease

SummaryTiclopidine (T) and aspirin (ASA) are two antiplatelet drugs both capable of prolonging bleeding time (BT), with a different mechanism of action. A synergism in BT prolongation has been reported and is currently considered an argument for not recommending their combination. However, a profound suppression of platelet function might be a desirable counterpart of a marked prolongation of BT, with a possible use in selected clinical situations. We therefore studied ex vivo platelet function (aggregation by ADP 0.5-1-2.5 μM; adrenaline 0.75-2.5 μM; collagen 1.5-150 μg/ml; arachidonic acid 1 mM; PAF 1 μM; adrenaline 0.17 μM + ADP 0.62 μM; serum thromboxane ([TX]B2 generation) and BT (Mielke) in 6 patients with stable coronary artery disease receiving such combination. Patients underwent sequential laboratory evaluations at baseline, after 7 days of T 250 mg b.i.d., before and after the intravenous administration of ASA 500 mg, respectively, and, finally, after a minimum of 7 days of sole ASA oral administration (50 mg/day). The experimental design, therefore, allowed a comparison of T and ASA effects (2nd and 4th evaluation), and an assessment of the combination effect (3rd evaluation). Platelet aggregation in response to all doses of ADP was depressed more by T than by ASA. Conversely, responses to adrenaline, and arachidonate were affected more by ASA than by T. For all other agents, differences were not significant. T + ASA combination was more effective (p <0.05) than either treatment alone in depressing responses to high-dose collagen (% over control, mean ± SEM: T: 95 ± 3; ASA: 96 ± 5; T + ASA: 89 ± 4). Serum TXB2 (basal, ng/ml: 380 ± 54) did not change with T (372 ± 36), dropped to <1 ng/ml on ASA injection and slightly re-increased to 9.1 ± 3.1 ng/ml on oral low-dose ASA. BT (basal 7.4 ± 0.6 min) was affected similarly by T (9.2 ± 0.8) or ASA (9.7 ± 0.9) alone, but increased to 15.0 ± 0.7 min on combination treatment (106% increase over control). Thus, the strong synergism in BT prolongation by ASA-T combination has a counterpart in the inhibition of platelet function in response to strong stimuli such as high-dose collagen, not otherwise affected significantly by single-drug treatment. This effect is a possible rationale for the clinical evaluation of T + ASA combination.

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Roles of IFN-γ in tumor progression and regression: a review

Biomarker Research ◽

10.1186/s40364-020-00228-x ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Dragica Jorgovanovic ◽

Mengjia Song ◽

Liping Wang ◽

Yi Zhang

Keyword(s):

Immune Response ◽

Tumor Progression ◽

Tumor Regression ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Interferon Γ ◽

High Dose ◽

Main Body ◽

Significant Research ◽

Ifn Γ

Abstract Background Interferon-γ (IFN-γ) plays a key role in activation of cellular immunity and subsequently, stimulation of antitumor immune-response. Based on its cytostatic, pro-apoptotic and antiproliferative functions, IFN-γ is considered potentially useful for adjuvant immunotherapy for different types of cancer. Moreover, it IFN-γ may inhibit angiogenesis in tumor tissue, induce regulatory T-cell apoptosis, and/or stimulate the activity of M1 proinflammatory macrophages to overcome tumor progression. However, the current understanding of the roles of IFN-γ in the tumor microenvironment (TME) may be misleading in terms of its clinical application. Main body Some researchers believe it has anti-tumorigenic properties, while others suggest that it contributes to tumor growth and progression. In our recent work, we have shown that concentration of IFN-γ in the TME determines its function. Further, it was reported that tumors treated with low-dose IFN-γ acquired metastatic properties while those infused with high dose led to tumor regression. Pro-tumorigenic role may be described through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, upregulation of indoleamine 2,3-dioxygenase, and checkpoint inhibitors such as programmed cell death ligand 1. Conclusion Significant research efforts are required to decipher IFN-γ-dependent pro- and anti-tumorigenic effects. This review discusses the current knowledge concerning the roles of IFN-γ in the TME as a part of the complex immune response to cancer and highlights the importance of identifying IFN-γ responsive patients to improve their sensitivity to immuno-therapies.

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Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation

Blood ◽

10.1182/blood.v95.11.3548 ◽

2000 ◽

Vol 95 (11) ◽

pp. 3548-3554 ◽

Cited By ~ 51

Author(s):

Antonio Condino-Neto ◽

Peter E. Newburger

Keyword(s):

B Cell ◽

Chronic Granulomatous Disease ◽

Cell Line ◽

Interferon Gamma ◽

Granulomatous Disease ◽

First Intron ◽

Cybb Gene ◽

Nuclear Rna ◽

Ifn Γ

Abstract X-linked chronic granulomatous disease (CGD) derives from defects in the CYBB gene, which encodes the gp91-phox component of NADPH oxidase. We studied the molecular basis of the disease in a kindred with variant CGD, due to a single base substitution at the sixth position of CYBB first intron. The patients' phagocytes have been shown previously to greatly increase superoxide release in response to interferon-gamma (IFN-γ) in vitro and in vivo. We examined CYBB gene expression in an Epstein-Barr virus (EBV)-transformed B-cell line from 1 patient in this kindred. These cells showed markedly decreased levels of CYBB transcripts in total RNA (5% of normal) and nuclear RNA (1.4% of normal), despite equal CYBB transcription rates in the CGD and control cells. Incubation with IFN-γ produced a 3-fold increase in CYBBtotal messenger RNA (mRNA) levels in the patient's cells, and decreased nuclear transcripts to undetectable levels. Reverse transcriptase–polymerase chain reaction analysis of RNA splicing revealed a preponderance of unspliced CYBB transcripts in the patient's nuclear RNA. In vitro incubation with IFN-γ increased by 40% the ratio of spliced relative to unspliced CYBB mRNA in nuclei from the CGD B-cell line. Total RNA harvested from the same patient's monocytes, on and off therapy with IFN-γ, showed a similar improvement in splicing. We conclude that IFN-γ partially corrects a nuclear processing defect due to the intronic mutation in theCYBB gene in this kindred, most likely by augmentation of nuclear export of normal transcripts, and improvement in the fidelity of splicing at the first intron.

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Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000247 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000247

Author(s):

Brett A Schroeder ◽

Ralph Graeme Black ◽

Sydney Spadinger ◽

Shihong Zhang ◽

Karan Kohli ◽

...

Keyword(s):

T Cell ◽

Interferon Gamma ◽

Low Dose ◽

Cellular Therapy ◽

Tumor Regression ◽

High Dose ◽

Adoptive Cellular Therapy ◽

Link Type ◽

T Cell Infiltration ◽

Ifn Γ

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

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Attenuation of Thrombosis by Crude Rice (Oryza sativa) Bran Policosanol Extract:Ex VivoPlatelet Aggregation and Serum Levels of Arachidonic Acid Metabolites

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7343942 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Wai-Teng Wong ◽

Maznah Ismail ◽

Eusni Rahayu Mohd Tohit ◽

Rasedee Abdullah ◽

Yi-Da Zhang

Keyword(s):

Platelet Aggregation ◽

Rice Bran ◽

Low Dose ◽

Ex Vivo ◽

Vascular Occlusion ◽

Full Blood Count ◽

Tween 20 ◽

High Dose ◽

Sprague Dawley ◽

Coagulation Time

Background. Vascular occlusion or thrombosis was often attributed to uncontrolled platelet activation. Influence of sugarcane policosanol extract on platelet was reported but little was known of rice bran policosanol, particularly its mechanisms of actions on platelet activities.Objective. Antiplatelet mechanisms of rice bran policosanol extract (RBE) were studied using hyperlipidemic Sprague Dawley rats.Ex vivoplatelet aggregation, platelet count (PC), bleeding time (BT), and coagulation time were assayed. Serum eicosanoids and other aggregation-related metabolites levels were quantified.Design. Rats were divided into 6 groups for comparisons (vehicle control Tween 20/H2O, high dose policosanol 500 mg/kg, middle dose policosanol 250 mg/kg, low dose policosanol 100 mg/kg, and positive control aspirin 30 mg/kg).Results. Low dose 100 mg/kg of RBE inhibited aggregation by42.32±4.31% and this was comparable with the effect of 30 mg/kg aspirin,43.91±5.27%. Results showed that there were no significant differences in PC, BT, and coagulation time among various groups after RBE treatment. Serum thromboxane A2was attenuated while prostacyclin level increased upon RBE treatment.Conclusions. RBE reducedex vivoADP-induced platelet aggregation without giving adverse effects. No changes in full blood count suggested that rice bran policosanol did not disturb biological blood cell production and destruction yet it reduced aggregation through different mechanisms.

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