Widespread intradermal accumulation of mononuclear leukocytes in lepromatous leprosy patients treated systemically with recombinant interferon gamma.

Intradermal administration of recombinant interferon gamma (rIFN-gamma) to lepromatous leprosy patients has converted the local histology toward a tuberculoid pattern. However, such changes have been confined to the site of injection. In contrast, in the present study, marked, intradermal accumulation of CD3+, CD4+, CD8+, and CD1a+ T cells and Leu-M5+ mononuclear phagocytes was induced at a distance from the sites of administration, in a dose-dependent manner, by 10 daily intramuscular injections of 10-30 micrograms rIFN-gamma/m2. Mononuclear cell infiltration began within 3 d of onset of rIFN-gamma therapy and persisted at least 8 wk. Intramuscular administration of rIFN-gamma to lepromatous patients receiving concurrent chemotherapy can safely induce widespread histologic features of an upgrading reaction.

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

Journal of Experimental Medicine ◽

10.1084/jem.173.3.767 ◽

1991 ◽

Vol 173 (3) ◽

pp. 767-770 ◽

Cited By ~ 27

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.

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LEPROMATOUS LEPROSY TREATED WITH RECOMBINANT INTERFERON GAMMA: CUTANEOUS HISTOLOGIC CHANGES

International Journal of Dermatology ◽

10.1111/j.1365-4362.1992.tb04253.x ◽

1992 ◽

Vol 31 (11) ◽

pp. 813-817 ◽

Cited By ~ 2

Author(s):

OSCAR BOTTASSO ◽

SANTIAGO BESUSCHIO ◽

VICTOR MERLIN ◽

JULIO C. MORINI ◽

JORGE BERNABO ◽

...

Keyword(s):

Interferon Gamma ◽

Lepromatous Leprosy ◽

Recombinant Interferon ◽

Histologic Changes

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Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon receptor immunoadhesin

Blood ◽

10.1182/blood.v83.4.911.bloodjournal834911 ◽

1994 ◽

Vol 83 (4) ◽

pp. 911-915 ◽

Cited By ~ 1

Author(s):

RT Jr Means ◽

SB Krantz ◽

J Luna ◽

SA Marsters ◽

A Ashkenazi

Keyword(s):

Animal Model ◽

Interferon Gamma ◽

Colony Formation ◽

Interleukin 1 ◽

Inhibitory Effect ◽

Dependent Manner ◽

Ifn Gamma ◽

Dose Dependent

It has been previously reported that inhibition of human erythroid colony-forming units (CFU-E) in vitro by interleukin-1 (IL-1) is an indirect effect, occurring through the production of interferon gamma (IFN gamma). IFN gamma, in turn, inhibits CFU-E colony formation directly, and its inhibitory effect can be overcome by exposure to high concentrations of erythropoietin (EPO). To develop an in vitro animal model for investigating inhibition of erythropoiesis by IFN gamma, the effects of recombinant murine (rm) IFN gamma on highly purified CFU-E from the spleens of mice infected with the anemia strain of the Friend virus (FVA) were studied. rmIFN gamma inhibited CFU-E colony formation in a dose-dependent manner. This inhibition occurred with large (> or = 8 cell) colonies only; smaller colonies were not affected. The inhibitory effect was corrected to 72% of control by high EPO concentrations of 64 U/mL. Murine CFU-E were then cultured with rmIFN gamma in the presence of a soluble murine IFN gamma receptor fused to the hinge and Fc domains of the human IgG1 heavy chain (mIFN gamma R-IgG). Inhibition of CFU-E colony formation by rmIFN gamma (100 U/mL) was corrected by mIFN gamma R-IgG in a dose-dependent manner, with an approximate IC50 of 0.05 nmol/L, and complete or near complete correction at 0.5 nmol/L. Similarly, a human IFN gamma R-IgG greatly reduced the inhibitory effect of recombinant human IFN gamma on human CFU-E. These experiments provide an in vitro animal model for studying the inhibitory effects of IFN gamma on erythropoiesis and indicate that IFN gamma R-IgG may be a useful agent for reducing the toxicity of IFN gamma in vivo.

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Synergistic effect of recombinant interferon-gamma and interleukin-3 on the growth of immature human hematopoietic progenitors

Blood ◽

10.1182/blood.v77.10.2118.2118 ◽

1991 ◽

Vol 77 (10) ◽

pp. 2118-2121 ◽

Cited By ~ 42

Author(s):

Y Kawano ◽

Y Takaue ◽

A Hirao ◽

T Abe ◽

S Saito ◽

...

Keyword(s):

Interferon Gamma ◽

Inhibitory Effect ◽

Human Interferon ◽

Dependent Manner ◽

Hematopoietic Progenitors ◽

Ifn Gamma ◽

Recombinant Interferon ◽

Interleukin 3 ◽

Liquid Suspension ◽

Colony Number

Abstract Purified peripheral blood hematopoietic progenitors from children in early remission from cancer respond to recombinant human interleukin-3 (IL-3), but not to granulocyte colony-stimulating factor (G-CSF). With these purified cells as a target, we studied the effect of recombinant human interferon-gamma (IFN-gamma) on progenitor growth, using both liquid-suspension limiting dilution assay (LDA) and regular methylcellulose culture of progenitors. We found that in LDA with IL-3, IFN-gamma directly stimulated the growth of blood progenitors in a dose- dependent manner with single-hit kinetics, whereas IFN-gamma suppressed the growth of G-CSF-supported progenitors obtained from bone marrow. The stimulatory effect was also observed in methylcellulose culture, but the addition of antibodies for G-CSF, granulocyte-macrophage CSF, IL-1 alpha, IL-1 beta, IL-6, or tumor necrosis factor did not result in a decrease of the colony number, supporting further the possible direct effect of IFN-gamma on progenitor growth. These results suggest that the inhibitory effect of IFN-gamma on hematopoietic progenitors is limited to those in an advanced stage of maturation. IFN-gamma may be one of the essential lymphokines upregulating the growth of human hematopoietic progenitor cells.

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Influence of interferon-gamma and extracellular tryptophan on indoleamine 2,3-dioxygenase activity in T24 cells as determined by a non-radiometric assay

Biochemical Journal ◽

10.1042/bj2560537 ◽

1988 ◽

Vol 256 (2) ◽

pp. 537-541 ◽

Cited By ~ 13

Author(s):

E R Werner ◽

G Werner-Felmayer ◽

D Fuchs ◽

A Hausen ◽

G Reibnegger ◽

...

Keyword(s):

Interferon Gamma ◽

Dependent Manner ◽

Indoleamine 2,3 Dioxygenase ◽

Cell Extracts ◽

T24 Cells ◽

Maximum Reaction ◽

Radiometric Assay ◽

Radioactive Assay ◽

Dose Dependent ◽

Dioxygenase Activity

The indoleamine 2,3-dioxygenase (EC 1.13.11.17) activity in human T24 cells has been investigated in cell extracts by using a non-radioactive assay. It is enhanced in a dose-dependent manner up to 25-fold by interferon-gamma. The maximum reaction velocity is increased rather than the Km, which remains at 4 mumol/l. Induction of activity starts 3 h after stimulation and reaches a plateau at 21-48 h. Decreased stimulation was observed in the presence of high L-tryptophan concentrations.

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A study of the effects of intradermal administration of recombinant gamma interferon in lepromatous leprosy patients

Leprosy Review ◽

10.5935/0305-7518.19870041 ◽

1987 ◽

Vol 58 (4) ◽

Cited By ~ 1

Author(s):

N. M. SAMUEL ◽

J. M. GRANGE ◽

S. SAMUEL ◽

S. LUCAS ◽

O. M. OWILLI ◽

...

Keyword(s):

Lepromatous Leprosy ◽

Gamma Interferon ◽

Intradermal Administration ◽

Leprosy Patients

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Interferon-gamma upregulates interleukin-8 gene expression in human monocytic cells by a posttranscriptional mechanism

Blood ◽

10.1182/blood.v83.2.537.bloodjournal832537 ◽

1994 ◽

Vol 83 (2) ◽

pp. 537-542

Author(s):

MC Bosco ◽

GL Gusella ◽

I Espinoza-Delgado ◽

DL Longo ◽

L Varesio

Keyword(s):

Gene Expression ◽

Interferon Gamma ◽

Mononuclear Phagocytes ◽

Interleukin 8 ◽

Dependent Manner ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Monocytic Cells ◽

Ifn Gamma ◽

Potent Inducer

Interleukin-8 (IL-8) is a neutrophil chemotactic and activating cytokine that is produced in response to several stimuli. Because monocytic cells are important producers of IL-8, we investigated whether interferon-gamma (IFN-gamma), a potent inducer of activation and differentiation of mononuclear phagocytes, affected IL-8 expression in this cell lineage. We found a low constitutive level of IL-8 mRNA expression that was upregulated by IFN-gamma in a dose- and time- dependent manner and via a protein-synthesis-dependent process in the human monocytic cell line U937. IL-8 protein secretion was also stimulated by IFN-gamma. Nuclear run-on experiments showed that the IL- 8 gene was transcriptionally active in control cells and that IFN-gamma did not enhance the transcriptional activity. The increase in IL-8 mRNA by IFN-gamma was concomitant with the stabilization of the mRNA and, therefore, controlled primarily at a posttranscriptional level. These results represent the first evidence that IFN-gamma upregulates IL-8 gene expression in cells of the monocytic lineage, and show the involvement of posttranscriptional mechanisms in the induction of IL-8 mRNA.

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Synergistic effect of recombinant interferon-gamma and interleukin-3 on the growth of immature human hematopoietic progenitors

Blood ◽

10.1182/blood.v77.10.2118.bloodjournal77102118 ◽

1991 ◽

Vol 77 (10) ◽

pp. 2118-2121 ◽

Cited By ~ 1

Author(s):

Y Kawano ◽

Y Takaue ◽

A Hirao ◽

T Abe ◽

S Saito ◽

...

Keyword(s):

Interferon Gamma ◽

Inhibitory Effect ◽

Human Interferon ◽

Dependent Manner ◽

Hematopoietic Progenitors ◽

Ifn Gamma ◽

Recombinant Interferon ◽

Interleukin 3 ◽

Liquid Suspension ◽

Colony Number

Purified peripheral blood hematopoietic progenitors from children in early remission from cancer respond to recombinant human interleukin-3 (IL-3), but not to granulocyte colony-stimulating factor (G-CSF). With these purified cells as a target, we studied the effect of recombinant human interferon-gamma (IFN-gamma) on progenitor growth, using both liquid-suspension limiting dilution assay (LDA) and regular methylcellulose culture of progenitors. We found that in LDA with IL-3, IFN-gamma directly stimulated the growth of blood progenitors in a dose- dependent manner with single-hit kinetics, whereas IFN-gamma suppressed the growth of G-CSF-supported progenitors obtained from bone marrow. The stimulatory effect was also observed in methylcellulose culture, but the addition of antibodies for G-CSF, granulocyte-macrophage CSF, IL-1 alpha, IL-1 beta, IL-6, or tumor necrosis factor did not result in a decrease of the colony number, supporting further the possible direct effect of IFN-gamma on progenitor growth. These results suggest that the inhibitory effect of IFN-gamma on hematopoietic progenitors is limited to those in an advanced stage of maturation. IFN-gamma may be one of the essential lymphokines upregulating the growth of human hematopoietic progenitor cells.

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Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon receptor immunoadhesin

Blood ◽

10.1182/blood.v83.4.911.911 ◽

1994 ◽

Vol 83 (4) ◽

pp. 911-915 ◽

Cited By ~ 33

Author(s):

RT Jr Means ◽

SB Krantz ◽

J Luna ◽

SA Marsters ◽

A Ashkenazi

Keyword(s):

Animal Model ◽

Interferon Gamma ◽

Colony Formation ◽

Interleukin 1 ◽

Inhibitory Effect ◽

Dependent Manner ◽

Ifn Gamma ◽

Dose Dependent

Abstract It has been previously reported that inhibition of human erythroid colony-forming units (CFU-E) in vitro by interleukin-1 (IL-1) is an indirect effect, occurring through the production of interferon gamma (IFN gamma). IFN gamma, in turn, inhibits CFU-E colony formation directly, and its inhibitory effect can be overcome by exposure to high concentrations of erythropoietin (EPO). To develop an in vitro animal model for investigating inhibition of erythropoiesis by IFN gamma, the effects of recombinant murine (rm) IFN gamma on highly purified CFU-E from the spleens of mice infected with the anemia strain of the Friend virus (FVA) were studied. rmIFN gamma inhibited CFU-E colony formation in a dose-dependent manner. This inhibition occurred with large (> or = 8 cell) colonies only; smaller colonies were not affected. The inhibitory effect was corrected to 72% of control by high EPO concentrations of 64 U/mL. Murine CFU-E were then cultured with rmIFN gamma in the presence of a soluble murine IFN gamma receptor fused to the hinge and Fc domains of the human IgG1 heavy chain (mIFN gamma R-IgG). Inhibition of CFU-E colony formation by rmIFN gamma (100 U/mL) was corrected by mIFN gamma R-IgG in a dose-dependent manner, with an approximate IC50 of 0.05 nmol/L, and complete or near complete correction at 0.5 nmol/L. Similarly, a human IFN gamma R-IgG greatly reduced the inhibitory effect of recombinant human IFN gamma on human CFU-E. These experiments provide an in vitro animal model for studying the inhibitory effects of IFN gamma on erythropoiesis and indicate that IFN gamma R-IgG may be a useful agent for reducing the toxicity of IFN gamma in vivo.

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Interferon-gamma upregulates interleukin-8 gene expression in human monocytic cells by a posttranscriptional mechanism

Blood ◽

10.1182/blood.v83.2.537.537 ◽

1994 ◽

Vol 83 (2) ◽

pp. 537-542 ◽

Cited By ~ 30

Author(s):

MC Bosco ◽

GL Gusella ◽

I Espinoza-Delgado ◽

DL Longo ◽

L Varesio

Keyword(s):

Gene Expression ◽

Interferon Gamma ◽

Mononuclear Phagocytes ◽

Interleukin 8 ◽

Dependent Manner ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Monocytic Cells ◽

Ifn Gamma ◽

Potent Inducer

Abstract Interleukin-8 (IL-8) is a neutrophil chemotactic and activating cytokine that is produced in response to several stimuli. Because monocytic cells are important producers of IL-8, we investigated whether interferon-gamma (IFN-gamma), a potent inducer of activation and differentiation of mononuclear phagocytes, affected IL-8 expression in this cell lineage. We found a low constitutive level of IL-8 mRNA expression that was upregulated by IFN-gamma in a dose- and time- dependent manner and via a protein-synthesis-dependent process in the human monocytic cell line U937. IL-8 protein secretion was also stimulated by IFN-gamma. Nuclear run-on experiments showed that the IL- 8 gene was transcriptionally active in control cells and that IFN-gamma did not enhance the transcriptional activity. The increase in IL-8 mRNA by IFN-gamma was concomitant with the stabilization of the mRNA and, therefore, controlled primarily at a posttranscriptional level. These results represent the first evidence that IFN-gamma upregulates IL-8 gene expression in cells of the monocytic lineage, and show the involvement of posttranscriptional mechanisms in the induction of IL-8 mRNA.

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