In vivo biological response to recombinant interferon-gamma during a phase I dose-response trial in patients with metastatic melanoma.

1990 ◽  
Vol 8 (6) ◽  
pp. 1070-1082 ◽  
Author(s):  
J M Kirkwood ◽  
M S Ernstoff ◽  
T Trautman ◽  
G Hebert ◽  
Y Nishida ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Dose Response ◽  
Dose Range ◽  
Cell Subset ◽  
Optimal Dosage ◽  
Antitumor Effects ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Wide Range

Interferon-gamma (IFN gamma), as produced by recombinant DNA technology, has shown a wide range of immunomodulatory activity in vitro and in vivo. Clinical studies have attempted to establish a dose-response relationship to define optimal dosage ranges for induction of effector cell function and host response in patients with cancer. We conducted a randomized trial to test the in vivo biologic activity of five daily dosages ranging from 3 to 3,000 micrograms/m2, administered by daily 2-hour bolus injection or by continuous infusion for 14 days. We demonstrate comparable immunobiologic effects of recombinant IFN gamma (rIFN gamma; Biogen, Inc, Cambridge, MA) administered by these two schedules at the various dosages tested, and have defined a relationship of dose to biologic response over this 3-log10 dose range. Oligo 2'5' adenylate synthetase (2'5'As) induction, natural-killer (NK) cell activity, and T-cell subset distribution (heightened T helper/suppressor ratio) showed the most consistent treatment-associated changes and the greatest immunobiologic effects at dosages of 300 to 1,000 micrograms/m2. Mononuclear cell DR and DQ antigen expression showed no consistent dose-related treatment effect. The relevance of the phenotypic, functional, and enzymologic effects observed in this trial to any clinical antitumor effects of IFN gamma in cancer therapy must now be established.

scholarly journals Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones.

1994 ◽  
Vol 179 (4) ◽  
pp. 1273-1283 ◽  
Author(s):  
R Manetti ◽  
F Gerosa ◽  
M G Giudizi ◽  
R Biagiotti ◽  
P Parronchi ◽  
...  
Keyword(s):  
T Cells ◽  
Interferon Gamma ◽  
Specific Antigen ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Gamma ◽  
Selection Of

Interleukin 12 (IL-12) facilitates the generation of a T helper type 1 (Th1) response, with high interferon gamma (IFN-gamma) production, while inhibiting the generation of IL-4-producing Th2 cells in polyclonal cultures of both human and murine T cells and in vivo in the mouse. In this study, we analyzed the effect of IL-12, present during cloning of human T cells, on the cytokine profile of the clones. The culture system used allows growth of clones from virtually every T cell, and thus excludes the possibility that selection of precommitted Th cell precursors plays a role in determining characteristics of the clones. IL-12 present during the cloning procedures endowed both CD4+ and CD8+ clones with the ability to produce IFN-gamma at levels severalfold higher than those observed in clones generated in the absence of IL-12. This priming was stable because the high levels of IFN-gamma production were maintained when the clones were cultured in the absence of IL-12 for 11 d. The CD4+ and some of the CD8+ clones produced variable amounts of IL-4. Unlike IFN-gamma, IL-4 production was not significantly different in clones generated in the presence or absence of IL-12. These data suggest that IL-12 primes the clone progenitors, inducing their differentiation to high IFN-gamma-producing clones. The suppression of IL-4-producing cells observed in polyclonally generated T cells in vivo and in vitro in the presence of IL-12 is not observed in this clonal model, suggesting that the suppression depends more on positive selection of non-IL-4-producing cells than on differentiation of individual clones. However, antigen-specific established Th2 clones that were unable to produce IFN-gamma with any other inducer did produce IFN-gamma at low but significant levels when stimulated with IL-12 in combination with specific antigen or insoluble anti-CD3 antibodies. This induction of IFN-gamma gene expression was transient, because culture of the established clones with IL-12 for up to 1 wk did not convert them into IFN-gamma producers when stimulated in the absence of IL-12. These results suggest that Th clones respond to IL-12 treatment either with a stable priming for IFN-gamma production or with only a transient low level expression of the IFN-gamma gene, depending on their stage of differentiation.

scholarly journals Anti-inflammatory activity of released-active antibodies to interferon-gamma, CD4-receptor, and histamine against respiratory-syncytial viral infection

2019 ◽  
pp. 85-89
Author(s):  
А.Г. Емельянова ◽  
С.А. Тарасов ◽  
С.Г. Морозов
Keyword(s):  
Interferon Gamma ◽  
Inflammatory Cells ◽  
Negative Control ◽  
Ifn Gamma ◽  
Cd4 Receptor ◽  
Cause Of Deaths ◽  
Prophylactic Use ◽  
Syncytial Virus ◽  
One Year

Актуальность. Респираторно-синцитиальный вирус (РСВ) вызывает наиболее опасные инфекции у детей, особенно до 1 года, являясь основной причиной смертельных исходов, и способствует развитию бронхиальной астмы. Эффективной терапии в отношении вызываемой им инфекции не существует, а меры профилактики ограничены. Перспективным может быть использование препаратов на основе релиз-активных антител (РА АТ), действие которых направлено на иммунные реакции организма. Целью работы являлось изучение эффектов РА АТ к ИФН-гамма, CD4-рецептору и гистамину при РСВ-инфекции in vivo при их профилактическом введении. Методы. Мышей линии Balb/c инфицировали интраназально РСВ в дозе 5 × 106 ТЦД50/мышь, в течение 5 суток до инфицирования животным вводили РА АТ к ИФН-гамма, CD4-рецептору и гистамину, или отрицательный контроль (вода очищенная). Через 6 суток после инфицирования оценивали инфильтрацию клеток воспаления в дыхательные пути. Результаты. РА АТ к ИФН-гамма, CD4-рецептору и гистамину статистически значимо (p < 0,05) снижают общую инфильтрацию клеток воспаления в легкие, а также уровень лимфоцитов и макрофагов по сравнению с контрольными группами. Заключение. Профилактическое применение РА АТ к ИФН-гамма, CD4-рецептору и гистамину способствует снижению выраженности воспаления дыхательных путей экспериментальных животных, зараженных РСВ. Background. Respiratory syncytial virus (RSV) causes the most dangerous infections in children, especially those under one year, being the main cause of deaths and contributing to the development of bronchial asthma. There is no effective treatment for the causative infection, and preventive measures are limited. The use of drugs based on released-active antibodies (RA Abs) that target the immune response may be promising. Aim. The aim of the work was to study preventive effects of RA Abs to interferon-gamma (IFN-gamma), CD4 receptor, and histamine on RSV infection in vivo. Methods Balb /c mice were infected with RSV intranasally at a dose of 5 × 106 TCID50 per mouse. For 5 days prior to infection, RA Abs to IFN-gamma, CD4 receptor, and histamine or the negative control (purified water) were intragastrically administered to the animals. Infiltration of inflammatory cells into the respiratory tract was evaluated 6 days after infection. Results. RA Abs to IFN-gamma, CD4 receptor, and histamine significantly (p < 0.05) reduced the total infiltration of inflammatory cells into the lungs, as well as levels of lymphocytes and macrophages compared with the control groups. Conclusion. The prophylactic use of RA Abs to IFN-gamma, CD4 receptor, and histamine helps to alleviate severity of airway inflammation in experimental animals infected with RSV.

Study of dosimetric characteristics of a commercial optically stimulated luminescence system

2017 ◽  
Vol 16 (4) ◽  
pp. 461-475 ◽  
Author(s):  
Gourav K. Jain ◽  
Arun Chougule ◽  
Ananth Kaliyamoorthy ◽  
Suresh K. Akula
Keyword(s):  
Dose Response ◽  
Response Curve ◽  
Light Exposure ◽  
Dose Range ◽  
Optically Stimulated Luminescence ◽  
Dose Response Curve ◽  
Field Size ◽  
In Vivo Dosimetry ◽  
Detector Response

AbstractBackgroundOptically stimulated luminescence dosimeters (OSLDs) have a number of advantages in radiation dosimetry making them an excellent dosimeter for in vivo dosimetry. The study aimed to study the dosimetric characteristics of a commercial optically stimulated luminescence (OSL) system by Landauer Inc., before using it for routine clinical practice for in vivo dosimetry in radiotherapy. Further, this study also aimed to investigate the cause of variability found in the literature in a few dosimetric parameters of carbon-doped aluminium oxide (Al2O3:C).Materials and methodsThe commercial OSLD system uses Al2O3:C nanoDotTM as an active radiation detector and InLightTM microStar® as a readout assembly. Inter-detector response, energy, dose rate, field size and depth dependency of the detector response were evaluated for all available clinical range of photon beam energies in radiotherapy.ResultsInter-detector variation in OSLD response was found within 3·44%. After single light exposure for the OSL readout, detector reading decreased by 0·29% per reading. The dose linearity was investigated between dose range 50–400 cGy. The dose response curve was found to be linear until 250 cGy, after this dose, the dose response curve was found to be supra-linear in nature. OSLD response was found to be energy independent for Co60 to 10 MV photon energies.ConclusionsThe cause of variability found in the literature for some dosimetric characteristics of Al2O3:C is due to the difference in general geometry, construction of dosimeter, geometric condition of irradiation, phantom material and geometry, beam energy. In addition, the irradiation history of detector used and difference in readout methodologies had varying degree of uncertainties in measurements. However, the large surface area of the detector placed in the phantom with sufficient build-up and backscatter irradiated perpendicularly to incident radiation in Co60 beam is a good method of choice for the calibration of a dosimeter. Understanding the OSLD response with all dosimetric parameters may help us in estimation of accurate dose delivered to patient during radiotherapy treatment.

scholarly journals Human recombinant interferon gamma enhances neonatal polymorphonuclear leukocyte activation and movement, and increases free intracellular calcium.

1991 ◽  
Vol 173 (3) ◽  
pp. 767-770 ◽  
Author(s):  
H R Hill ◽  
N H Augustine ◽  
H S Jaffe
Keyword(s):  
Intracellular Calcium ◽  
Interferon Gamma ◽  
Messenger Rna ◽  
Intrinsic Defect ◽  
Mononuclear Leukocytes ◽  
Developmental Defect ◽  
Phagocytic Cells ◽  
Ifn Gamma ◽  
Recombinant Interferon ◽  
Free Intracellular Calcium

In previous studies, we have reported that after chemotactic factor stimulation, PMNs from neonates fail to undergo certain critical activation steps. Furthermore, the concentration of free intracellular calcium reached is significantly below that of PMNs from adults. Interferon-gamma (IFN-gamma) is a lymphokine that has been shown to activate phagocytic cells, and IFN-gamma messenger RNA production by neonatal mononuclear leukocytes has been reported to be depressed. In the present studies, we found that recombinant human IFN-gamma markedly enhanced the chemotactic responses of PMNs from neonates to levels that were not different from that of PMNs from adults. Furthermore, preincubation of the neonatal cells with this recombinant human lymphokine also corrected the abnormality in intracellular calcium metabolism. These results suggest that this developmental defect in phagocytic cell movement may be the result of an intrinsic defect in IFN-gamma production resulting in deficiency of this critical phagocyte-activating lymphokine.

scholarly journals Dose Range Evaluation of Liposomal Nystatin and Comparisons with Amphotericin B and Amphotericin B Lipid Complex in Temporarily Neutropenic Mice Infected with an Isolate of Aspergillus fumigatus with Reduced Susceptibility to Amphotericin B

1999 ◽  
Vol 43 (11) ◽  
pp. 2592-2599 ◽  
Author(s):  
David W. Denning ◽  
Peter Warn
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Dose Range ◽  
Respiratory Arrest ◽  
Optimal Dosage ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Liver And Kidney ◽  
Amphotericin B Lipid Complex

ABSTRACT Using an isolate of Aspergillus fumigatus that is less susceptible in vivo to amphotericin B than most other isolates, we compared different doses of liposomal nystatin (L-nystatin), liposomal amphotericin B (L-amphotericin), and amphotericin B lipid complex (ABLC) with amphotericin B deoxycholate. Four experiments with intravenously infected neutropenic mice were conducted. A dose of L-nystatin at 10 mg/kg of body weight was toxic (the mice had fits or respiratory arrest). The optimal dosage of L-nystatin was 5 mg/kg daily on days 1, 2, 4, and 7 (90% survival). This was superior to L-amphotericin (5 mg/kg [P = 0.24] and 1 mg/kg [P < 0.0001]), ABLC (5 mg/kg [P = 0.014] and 1 mg/kg [P < 0.0001]), and amphotericin B deoxycholate (5 mg/kg [P = 0.008]). In terms of liver and kidney cultures, L-nystatin (5 mg/kg) was superior to all other regimens (P = 0.0032 and <0.0001, respectively). Higher doses of L-amphotericin (25 and 50 mg/kg) in one earlier experiment were more effective (100% survival) than 1 mg of L-amphotericin per kg and amphotericin deoxycholate (5 mg/kg) in terms of mortality and both liver and kidney culture results and to L-amphotericin (5 mg/kg) in terms of liver and kidney culture results only. ABLC (25 mg/kg) given daily for 7 days was superior to ABLC (50 mg/kg [P = 0.03]) but not to ABLC at 5 mg/kg or amphotericin B deoxycholate in terms of mortality, although it was in terms of liver and kidney culture results. No dose-response for amphotericin B (5 and 1 mg/kg) was demonstrable. In conclusion, in this stringent model, high doses of L-amphotericin and ABLC could overcome reduced susceptibility to amphotericin B deoxycholate, but all were inferior to 5- to 10-fold lower doses of L-nystatin.

Phase I trial of recombinant interferon gamma in cancer patients.

1986 ◽  
Vol 4 (2) ◽  
pp. 137-146 ◽  
Author(s):  
S Vadhan-Raj ◽  
A Al-Katib ◽  
R Bhalla ◽  
L Pelus ◽  
C F Nathan ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Phase 1 ◽  
Rest Period ◽  
Lymphocytic Leukemia ◽  
Fixed Dose ◽  
Rapid Decline ◽  
Recombinant Interferon ◽  
Advanced Malignancy

Interferon gamma (IFN-gamma) is a lymphokine with potent in vitro effects on cell growth and immune function. We have investigated the effects of rIFN-gamma (sp act approximately 2 X 10(7) U/mg, purity greater than 99%) in 16 evaluable patients with advanced malignancy in a phase 1 trial. Patients were treated with six-hour intravenous (IV) infusions daily, five days a week for 2 weeks. After a 2-week rest period, the IV treatment cycle was repeated. Responders were maintained on repeated IV treatment cycles or daily intramuscular (IM) injections. Patients were entered at fixed dose levels of 0.1, 0.5, or 1.0 mg/m2/d. The maximum safely tolerated dose was 0.5 mg/m2. The most common side effects were constitutional symptoms, including fever, chills, fatigue, and myalgias. Reversible and transient increases in hepatic transaminase and decrease in granulocyte counts were seen. Treatment was associated with a dose-dependent increase in serum levels of beta 2 microglobulin. Partial responses (PRs) were observed in one patient with Hodgkin's disease and one patient with chronic lymphocytic leukemia. Fairly constant levels of serum IFN were found at four and six hours during infusion, followed by a rapid decline within one to two hours. We conclude that rIFN-gamma can be safely administered by a six-hour IV infusion and that it can induce in vivo some of the biologic effects reported in in vitro studies.

Placental MHC class I antigen expression is induced in mice following in vivo treatment with recombinant interferon-gamma

1991 ◽  
Vol 19 (2) ◽  
pp. 115-129 ◽  
Author(s):  
R. Mattsson ◽  
R. Holmdahl ◽  
A. Scheynius ◽  
F. Bernadotte ◽  
A. Mattsson ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Interferon Gamma ◽  
Antigen Expression ◽  
Class I ◽  
Recombinant Interferon ◽  
Mhc Class I Antigen ◽  
In Vivo Treatment

scholarly journals Interferon gamma inhibits apoptotic cell death in B cell chronic lymphocytic leukemia.

1993 ◽  
Vol 177 (1) ◽  
pp. 213-218 ◽  
Author(s):  
M Buschle ◽  
D Campana ◽  
S R Carding ◽  
C Richard ◽  
A V Hoffbrand ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Programmed Cell Death ◽  
B Cell ◽  
Interferon Gamma ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Ifn Gamma ◽  
Cell Chronic Lymphocytic Leukemia

The malignant, CD5+ B lymphocytes of B cell chronic lymphocytic leukemia (B-CLL) die by apoptosis in vitro. This is in contrast to the prolonged life span of the leukemic cells in vivo and likely reflects the lack of essential growth factors in the tissue culture medium. We found that interferon gamma (IFN-gamma) inhibits programmed cell death and promotes survival of B-CLL cells in culture. This effect may also be important in vivo: increased serum levels of IFN-gamma, ranging from 60 to &gt; 2,200 pg/ml, were found in 7 of 10 B-CLL samples tested, whereas the sera of 10 healthy individuals did not contain detectable levels of this cytokine (&lt; 20 pg/ml). High levels of IFN-gamma message were detected in RNA from T cell-depleted B-CLL peripheral blood samples by Northern blot analysis. Synthesis of IFN-gamma by B-CLL lymphocytes was confirmed by in situ hybridization and flow cytometry. The majority of B-CLL cells (74-82%) expressed detectable levels of IFN-gamma mRNA, and CD19+ B-CLL cells were labeled with anti-IFN-gamma monoclonal antibodies. These results show that IFN-gamma inhibits programmed cell death in B-CLL cells and suggest that the malignant cells are able to synthesize this cytokine. By delaying apoptosis, IFN-gamma may extend the life span of the malignant cells and thereby contribute to their clonal accumulation.

scholarly journals Recombinant interleukin 12 cures mice infected with Leishmania major.

1993 ◽  
Vol 177 (5) ◽  
pp. 1505-1509 ◽  
Author(s):  
F P Heinzel ◽  
D S Schoenhaut ◽  
R M Rerko ◽  
L E Rosser ◽  
M K Gately
Keyword(s):  
T Cell ◽  
Leishmania Major ◽  
Durable Resistance ◽  
Cell Subset ◽  
Host Responses ◽  
Interleukin 12 ◽  
Self Healing ◽  
T Lymphocyte Subsets ◽  
Ifn Gamma

Resistant C57BL/6 mice infected with Leishmania major are self-healing, whereas susceptible BALB/c mice fail to contain cutaneous infection and subsequently undergo fatal visceral dissemination. These disparate outcomes are mediated by dissimilar expansions of T helper type 1 (Th1) and Th2 CD4+ T lymphocyte subsets in vivo during cure and progression of disease. Because interleukin 12 (IL-12) has potent T cell growth and interferon gamma (IFN-gamma) stimulatory effects, we studied its effect on CD4+ T cell differentiation during murine leishmaniasis. Treatment with recombinant murine (rMu)IL-12 during the first week of infection cured 89% of normally susceptible BALB/c mice, as defined by decreased size of infected footpads and 1,000-10,000-fold reduced parasite burdens, and provided durable resistance against reinfection. Cure was associated with markedly depressed production of IL-4 by lymph node cells cultured with antigen or mitogen, but preserved or increased production of IFN-gamma relative to untreated mice. IL-4 and IFN-gamma mRNA associated with CD4+ T lymphocytes isolated from infected lymph nodes showed similar reciprocal changes in response to rMuIL-12 therapy. A single injection of anti-IFN-gamma monoclonal antibody abrogated the protective effect of rMuIL-12 therapy and restored Th2 cytokine responses. We conclude that rMuIL-12 prevents deleterious Th2 T cell responses and promotes curative Th1 responses in an IFN-gamma-dependent fashion during murine leishmaniasis. Since BALB/c leishmaniasis cannot be cured with rMuIFN-gamma alone, additional direct effects of IL-12 during T cell subset selection are suggested. Because rMuIL-12 is uniquely protective in this well-characterized model of chronic parasitism, differences in IL-12 production may underlie heterogenous host responses to L. major and other intracellular pathogens.

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