Biological effects of γ‐interferon on human tumor cells: Quantity and affinity of cell membrane receptors for γ‐IFN in relation to growth inhibition and induction of HLA‐DR expression

Üçer, U.; Bartsch, H. H.; Scheurich, Peter; Pfizenmaier, Klaus

doi:10.1002/ijc.2910360116

Cited by 65 publications

(22 citation statements)

References 17 publications

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“…In addition, blood was drawn in heparinized tubes and PBMNC were isolated by Ficoll-hypaque density centrifugation and membrane receptors for IFN-y and IFN-(y were determined by binding of radioiodinated interferons (Ucer et al, 1985). For comparison, normal granulocytes and bonemarrow cells from healthy individuals were isolated with NIMmedium.…”

Section: Patient Evaluation and Laboratory Parametersmentioning

confidence: 99%

Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: Clinical responsiveness to recombinant ifn‐α correlates with the degree of receptor down‐regulation

Bartsch

Pfizenmaier

Hanusch

et al. 1989

Intl Journal of Cancer

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Natural and recombinant interferons (IFNs) have already demonstrated therapeutic efficacy, including cytogenetic remissions, in patients with chronic myelocytic leukemia (CML). We investigated at the level of ligand-receptor interaction the question whether heterogeneity of receptor number or affinity might contribute to primary or secondary treatment failures in CML. We therefore analyzed IFN-gamma and IFN-alpha receptor expression and regulation during treatment with recombinant IFN-gamma and IFN-alpha in 15 patients with advanced CML. We found no difference in number or affinity of constitutively expressed IFN-gamma receptors (mean 1,100) and, on average, a 30% reduction of IFN-alpha receptors (mean 750) on peripheral blood mononuclear cells (PBMNC) of patients with chronic or accelerated CML as compared to mature granulocytes and/or bone marrow cells of healthy controls, which express on average 1,050 and 1,100 IFN-gamma and IFN-alpha receptors, respectively. While IFN-gamma receptor expression on PBMNC is not influenced upon treatment with rIFN-gamma, there is a substantial downregulation of IFN-alpha receptors in the course of rIFN-alpha therapy. Our data also show a differential pattern of receptor downregulation between patients achieving complete hematologic remission (CHR) (4 out of 12) compared with patients with partial hematologic remission (PHR) and non-responders. We conclude that differences in IFN receptor number cannot explain primary or secondary treatment failures. However, the differential ligand induced downregulation of IFN-alpha receptors in patients achieving CHR compared to those with PHR or non-responders suggest a prospective value of IFN-alpha receptor determination.

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Section: Patient Evaluation and Laboratory Parametersmentioning

confidence: 99%

Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: Clinical responsiveness to recombinant ifn‐α correlates with the degree of receptor down‐regulation

Bartsch

Pfizenmaier

Hanusch

et al. 1989

Intl Journal of Cancer

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“…Human and murine IFN-y share 40%o amino acid sequence identity (22) and exhibit species specificity with respect to receptor binding (15,52) and biological activity (14,22). Human and murine IFN--y receptor (hIFN--yR and mIFN--yR, respectively) cDNAs have been cloned and expressed (2,12,23,25,32,39).…”

mentioning

confidence: 99%

The extracellular domain of the human interferon gamma receptor interacts with a species-specific signal transducer.

Gibbs¹,

Williams²,

Gray³

et al. 1991

Mol. Cell. Biol.

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At least two species-specific gene products are required for signal transduction by interferon gamma (IFN-y). The first is the IFN-y receptor, which binds ligand with high affinity in a species-specific manner. The second is an undetermined species-specific signal transducer(s). To determine whether the human IFN-y receptor (hIFN--yR) IFN-,y binds with high affinity (Kd = 10-9 to 10-11 M at 4°C) to a 90-kDa glycoprotein receptor present in low numbers (102 to 104) on a wide variety of cell types (7,16,19,33,36,42,51). Human and murine IFN-y share 40%o amino acid sequence identity (22) and exhibit species specificity with respect to receptor binding (15, 52) and biological activity (14,22). Human and murine IFN--y receptor (hIFN--yR and mIFN--yR, respectively) cDNAs have been cloned and expressed (2,12,23,25,32,39 affinity to the hIFN-yR but no biological response is elicited. The hIFN-yR as expressed in murine somatic cell hybrids and transfected mouse cells has binding properties similar to those of the hIFN--yR on human cells (1,7,36,42). These findings, in conjunction with results of cross-linking experiments (7,19,36,40), suggest that in contrast to the interleukin-6 (26, 54) and granulocyte-macrophage colony-stimulating factor receptors (21, 24), a second IFN--yR chain is not involved in mediating high-affinity ligand binding.Human-murine somatic cell hybrids containing human chromosomes 6 and 21 (29), as well as human-hamster and human-murine somatic cell hybrids containing human chromosome 21 and transfected with hIFN--yR expression vectors (17, 28), respond to hIFN-y as measured by the induction of MHC class I antigen. These findings demonstrate that the human chromosome 21-encoded factor(s) is necessary for signalling by the hIFN-yR, at least with respect to histocompatibility antigen expression, and suggest that the signal transducer(s) and the IFN-yR must be from the same species. How these two species-specific molecules function is unknown.To determine the region(s) of the IFN-yR that must be from the same species as the signal transducer to generate a functional response to IFN-y, we constructed expression vectors for human and hybrid human-murine IFN-y receptors. We transfected each expression vector into two different murine cell lines, one of which (SCC-16-5) contains a single copy of human chromosome 21. Transfectants were stimulated with hIFN-y and analyzed for increased expression of murine MHC class I antigen. Using this approach, we identified the region of the IFN--yR that cooperates with the species-specific signalling element(s).

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“…4). Because the biological activity of IFN-␥ in a given cell line correlates with that cell line's level of IFN-␥ receptor expression (Ucer et al, 1985), this may explain the greater sensitivity of T84 monolayers to IFN-␥ in our experiments.…”

Section: Downloaded Frommentioning

confidence: 94%

Interferon-γ Released by Gluten-Stimulated Celiac Disease-Specific Intestinal T Cells Enhances the Transepithelial Flux of Gluten Peptides

Bethune¹,

Siegel²,

Howles-Banerji³

et al. 2009

J Pharmacol Exp Ther

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Celiac sprue is a T-cell-mediated enteropathy elicited in genetically susceptible individuals by dietary gluten proteins. To initiate and propagate inflammation, proteolytically resistant gluten peptides must be translocated across the small intestinal epithelium and presented to DQ2-restricted T cells, but the effectors enabling this translocation under normal and inflammatory conditions are not well understood. We demonstrate that a fluorescently labeled antigenic 33-mer gluten peptide is translocated intact across a T84 cultured epithelial cell monolayer and that preincubation of the monolayer with media from gluten-stimulated, celiac patient-derived intestinal T cells enhances the apical-to-basolateral flux of this peptide in a dosedependent, saturable manner. The permeability-enhancing activity of activated T-cell media is inhibited by blocking antibodies against either interferon-␥ or its receptor and is recapitulated using recombinant interferon-␥. At saturating levels of interferon-␥, activated T-cell media does not further increase transepithelial peptide flux, indicating the primacy of interferon-␥ as an effector of increased epithelial permeability during inflammation. Reducing the assay temperature to 4°C reverses the effect of interferon-␥ but does not reduce basal peptide flux occurring in the absence of interferon-␥, suggesting active transcellular transport of intact peptides is increased during inflammation. A panel of disease-relevant gluten peptides exhibited an inverse correlation between size and transepithelial flux but no apparent sequence constraints. Anti-interferon-␥ therapy may mitigate the vicious cycle of gluten-induced interferon-␥ secretion and interferon-␥-mediated enhancement of gluten peptide flux but is unlikely to prevent translocation of gluten peptides in the absence of inflammatory conditions.

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Biological effects of γ‐interferon on human tumor cells: Quantity and affinity of cell membrane receptors for γ‐IFN in relation to growth inhibition and induction of HLA‐DR expression

Cited by 65 publications

References 17 publications

Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: Clinical responsiveness to recombinant ifn‐α correlates with the degree of receptor down‐regulation

Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: Clinical responsiveness to recombinant ifn‐α correlates with the degree of receptor down‐regulation

The extracellular domain of the human interferon gamma receptor interacts with a species-specific signal transducer.

Interferon-γ Released by Gluten-Stimulated Celiac Disease-Specific Intestinal T Cells Enhances the Transepithelial Flux of Gluten Peptides

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