Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.
BIOLOGICAL RESPONSE MODIFICATION IN MAN: MEASUREMENT OF INTERFERON-INDUCED PROTEINS
The Interferon System. A Current Review to 1987. Baron S et al, eds. The University of Texas Medical Branch Series in Biomedical Science, Austin, TX, University of Texas Press, p. 423-9, 1987.. Unique Identifier : AIDSLINE ICDB/89650511 Borden E; Paulnock D; Spear G; Byrne G; Merritt J; Brown R; Dept. of Human Oncology, Univ. of Wisconsin, Madison, WI 53792
Abstract:
Interferons (IFNs)--prototypic biological response modifiers--are the first such modifiers prepared by recombinant DNA technology to impact on treatment of human disease. The authors focus on changes in levels of major histocompatibility (MHC) proteins, 2-5A synthetase, and indoleamine-2,3-dioxygenase, as induced in vivo by human IFN. The protein first identified as increasing in patients (pts) receiving IFN was beta 2 microglobulin, a molecule associated with cell surface MHC proteins. IFN-alpha, at doses of 10 million units, resulted in increased serum beta 2 microglobulin; with continued daily im administration of the IFN-alpha, the protein remained increased over the baseline. After daily im injections of IFN-gamma, 2- to 5-fold enhancement in serum beta 2 microglobulin was observed in 17/20 specimens. Increases in beta 2 microglobulin were also found on peripheral mononuclear cells (PMC) after im administration of IFN-alpha; the increase was associated with a small lymphocyte fraction. In addition, increased beta 2 expression was demonstrated on monocytes after administration of IFN-beta(ser) or IFN-gamma. Enhanced MHC Class I protein expression on peripheral lymphocytes was identified 24 hr after im administration of 50 million units of IFN-alpha A, and enhanced Class II components on monocytes were shown within 48 hr after initiation of 3-30 million units of IFN-beta administered iv. While the exact role of the 2-5A synthetase system in the biologic activity of IFN is not clear, increase in 2-5A synthetase activity has been a sensitive indicator of in vitro treatment with IFN. PMC exhibit relatively low but consistent levels of 2-5A synthetase, but after im injections of IFN-alpha the activity in such cells rose approx 2- to 10-fold. In AIDS pts, however, the IFN-alpha did not regularly produce an increase in 2-5A synthetase over pretreatment levels. With regard to indoleamine-2,3-dioxygenase activity, it has been reported that, when levels of tryptophan in plasma were measured in pts who had received iv injections of IFN-gamma as part of a Phase I clinical trial, decreases in tryptophan levels were observed relative to pretreatment values or values obtained from individuals who had received iv injections of human IFN-alpha. Urine samples from pts who received the IFN-gamma had elevated kynurenine levels relative to pretreatment levels. In in vitro studies, human lung fibroblasts that were treated with various concentrations of IFN-gamma were found to degrade tryptophan in a dose- and time-dependent manner; similarly, human bladder carcinoma cells were induced to catabolize tryptophan after incubation with IFN-gamma but not with IFN-beta(ser) or IFN-alpha. Tryptophan degradation was thus induced in vitro and in vivo in response to exogenous IFN-gamma. (17 Refs)
Keywords: beta 2-Microglobulin/BIOSYNTHESIS Cells, Cultured Drug Evaluation Enzyme Induction Human Interferon Type I/PHARMACOLOGY Interferon Type II/PHARMACOLOGY Interferons/*PHARMACOLOGY Major Histocompatibility Complex Oxygenases/BIOSYNTHESIS Proteins/*BIOSYNTHESIS 2',5'-Oligoadenylate Synthetase/BIOSYNTHESIS MONOGRAPH REVIEW REVIEW, TUTORIAL
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Important note: Information in this article was accurate in 1989. The state of the art may have changed since the publication date.
