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PubMed1999

Early prediction of response in interferon monotherapy and in interferon-ribavirin combination therapy for chronic hepatitis C: HCV RNA at 4 weeks versus ALT.

BACKGROUND/AIMS: There is consensus that interferon for hepatitis C should be stopped if alanine aminotransferase (ALT) remains elevated after 12 weeks; however, this may lead to unjust treatment withdrawal in around 20% of potential sustained responders. No consensus exists for interferon-ribavirin combination therapy. The aim of this study was to assess the predictive value of an HCV RNA test at 4 weeks in comparison with ALT, both in interferon monotherapy and in interferon-ribavirin combination therapy. METHODS: Plasma HCV RNA was tested at 4 weeks in 149 naive patients undergoing 6 months and 187 undergoing up to 12 months of interferon monotherapy, and in 40 non-responders treated for 6 months with interferon-ribavirin combination therapy. RESULTS: For 6 and up to 12 months of interferon monotherapy, the predictive value for non-response was 99% resp. 97% for a positive HCV RNA at week 4, versus 97% resp. 91% for an elevated ALT at week 12. Using a positive HCV RNA at week 4 as a stopping rule would lead to missing 5% resp. 12% of potential sustained responders, versus 10% resp. 28% for an elevated ALT at week 12. In interferon-ribavirin combination therapy, the predictive value for non-response was 100% for week 4 HCV RNA versus 95% for week 12 ALT, and 0% potential sustained responders were missed by a test for week 4 HCV RNA versus 20% for week 12 ALT. The overall sensitivity and specificity of a week 4 HCV RNA test was significantly better (area under ROC 0.85) as compared to testing ALT at week 4 (0.78, p<0.001), week 8 (0.76, p<0.001) or week 12 (0.78, p<0.001). CONCLUSION: A positive HCV RNA test (> or =10(3) copies/ ml) at 4 weeks is highly predictive for non-response and leads to significantly less misidentification of potential sustained responders than ALT at week 4, 8 or 12, both in 6 or up to 12 months interferon monotherapy and in 6 months interferon-ribavirin combination therapy of chronic hepatitis C.

Alanine Transaminase↗
PubMed2002

A randomized trial of high-dose interferon alpha-2b, with or without ribavirin, in chronic hepatitis C patients who have not responded to standard dose interferon.

BACKGROUND: Conventional interferon monotherapy fails to achieve virological clearance in most hepatitis C-infected patients. The use of high-dose induction regimens may improve the initial clearance of virus, while the addition of ribavirin appears to improve the rates of sustained response once clearance is achieved. AIM: To compare the efficacy and safety of re-treatment with an induction regimen of high-dose interferon alpha-2b, with or without ribavirin, in chronic hepatitis C patients who have not responded to standard dose interferon monotherapy. METHODS: Previous virological non-responders to standard dose interferon (3-5 MU three times weekly for > or = 12 weeks) were randomized to receive, unblind, either 10 MU interferon alpha-2b daily for 10 days, then 5 MU daily for 74 days, then 5 MU three times weekly for 24 weeks (total 36 weeks) (group A), or the above regimen with the addition of ribavirin, 1000-1200 mg/day, at day 11 (group B). All patients were followed up for 24 weeks after completion of therapy. RESULTS: End of treatment virological response was noted in one of 10 (10%) patients in group A and in eight of 15 (54%) patients in group B (P=0.04). The sole end treatment responder in group A and three in group B relapsed on follow-up. The apparent improvement in response in group B compared to group A nearly reached statistical significance (group B 5/15 vs. group A 0/10; P=0.06). CONCLUSIONS: In this small pilot study, a 36-week high-dose induction interferon monotherapy protocol did not yield sustained responses in previous non-responders to standard dose interferon. However, the same regimen with ribavirin yielded a 33% sustained response rate, nearly reaching statistical significance. The therapy was well tolerated, despite the higher doses of interferon used and the addition of ribavirin. High-dose interferon with ribavirin appears to be a therapeutic option for non-responders to conventional interferon monotherapy.

Adult↗
PubMed1978

The mode of production of endotoxin-induced interferon in rabbit tissue cells. I. Development of priming by pretreatment with interferon.

In vitro production of endotoxin-induced interferon in rabbit tissue cell cultures could be enhanced by pretreatment with interferon. The enhancible state developed from the first hr of incubation at 37 C and a maximal priming effect was attained at 6 hr of incubation. Yields of interferon from unprimed cultures were usually 20-200 units/ml. In contrast, the primed cultures constantly yielded 1,000-2,500 units/ml of interferon. The pretreatment with interferon seemed to cause an earlier appearance of detectable interferon and the primed cells became more sensitive to endotoxin. It turned out that 10--30 units/ml of rabbit interferon were enough to develop the maximal priming. Even when cells were pretreated with higher doses of rabbit interferon such as 1.0 x 10(4) - 1.0 x 10(5) units/ml, the same level of priming effect was always observed without diminution. Various types of homologous (rabbit) and heterologous (human and mouse) interferon preparations showed similar dose-dependent enhancement of interferon production in proportion to the antiviral titers of these preparations as tested with RK-13 cells of rabbit origin.

Animals↗
PubMed1986

A monoclonal antibody with broad reactivity to human interferon-alpha subtypes useful for purification of leukocyte-derived interferon.

A monoclonal antibody to human interferon-alpha, termed HT-1 antibody, with a broad reactivity to various subtypes of interferon-alpha was prepared. It bound and neutralized all of the four subtypes of E. coli-derived human recombinant interferon-alpha (alpha 1, alpha 2, alpha 4, and alpha 6) tested; it also neutralized human natural leukocyte interferon but only partially. Human interferon-beta and -gamma were not bound. The antibody conjugated to Sepharose beads retained over 90% of human leukocyte interferon induced by Sendai virus. The bound interferon was recovered by acid elution in good yields and in almost pure form (specific activity was about 2 X 10(8) international units/mg protein). The purified interferon showed, in SDS-polyacrylamide gel electrophoresis, an activity profile with major peaks in a mol. wt. range of 17,000-22,000, which completely agreed with the profile shown by polyclonal antibody-purified interferon. Such purified leukocyte interferon-alpha preparations containing most of the naturally occurring subtypes can be useful for clinical and other purposes.

Animals↗
PubMed2006

48 weeks pegylated interferon alpha-2a is superior to 24 weeks of pegylated interferon alpha-2b in achieving hepatitis B e antigen seroconversion in chronic hepatitis B infection.

BACKGROUND/AIM: Although 48-week therapy with pegylated-interferons has been shown to be effective for the treatment of chronic hepatitis B virus infection, the efficacy of a shorter duration of therapy with pegylated interferons is unknown. METHOD: We reviewed 53 hepatitis B e antigen positive Chinese patients treated with 48 weeks of pegylated interferon alpha-2a or 24 weeks of pegylated interferon alpha-2b. Sustained virological response was defined as hepatitis B e antigen seroconversion and hepatitis B virus DNA <10(5) copies/mL at week 72. RESULTS: Twenty-nine patients were treated with 48 weeks of pegylated-interferon-alpha-2a and 24 patients with 24 weeks of pegylated-interferon-alpha-2b. At the end-of-therapy, hepatitis B e antigen seroconversion and hepatitis B virus DNA <10(5) copies/mL were similar between the two groups of patients [9/29 (31.0%) vs. 2/24 (8.3%), respectively, P = 0.09]. At week 72, 10 of the 29 patients (34.5%) treated with 48 weeks of pegylated-interferon-alpha-2a compared with two of the 24 patients (8.3%) treated with 24 weeks of pegylated-interferon-alpha-2b had sustained virological response (P = 0.04). By logistic analysis, 48 weeks of pegylated-interferon-alpha-2a was independently associated with sustained virological response (P = 0.04 adjusted hazards-ratio 9.37). CONCLUSION: Further studies are required to determine the optimal duration of therapy with pegylated interferons in chronic hepatitis B.

Adult↗
PubMed1985

Differential regulation of interferon-induced mRNAs and c-myc mRNA by alpha- and gamma-interferons.

The extent and kinetics of induction have been determined for eight mRNAs induced by alpha- and gamma-interferons in HeLa cells. The mRNAs which code for a 2-5A synthetase, metallothionein II, HLA class I antigen and five unknown proteins were induced 2 - greater than 100-fold by alpha-interferons. In the continued presence of alpha-interferon some mRNAs were maintained at the induced levels until at least 40 h, whereas others were induced only transiently. When the effects of alpha- and gamma-interferons were compared, the induced levels and kinetics were very similar for one mRNA (1-8) but were significantly different for the others. One mRNA (6-16) was induced more than 100-fold by alpha-interferon but not significantly by gamma-interferon. Parallel analysis of the level of c-myc mRNA showed it to decrease twofold in response to alpha-interferon, but to increase more than threefold in response to gamma-interferon, despite a more profound inhibition of cell growth by the latter. There must, therefore, be differences in how the levels of different mRNAs are sustained by alpha-interferons and how alpha- and gamma-interferons regulate the levels of the same mRNAs.

Cloning, Molecular↗
PubMed2000

Treatment of chronic hepatitis C in patients who failed interferon monotherapy: effects of higher doses of interferon and ribavirin combination therapy. The Virginia Cooperative Hepatitis Treatment Group.

OBJECTIVE: The present study was designed to evaluate the effectiveness of interferon-ribavirin combination therapy for treatment of chronic hepatitis C virus (HCV) in patients who failed previous treatment with interferon monotherapy. METHODS: A total of 140 patients with well-documented chronic HCV who failed to achieve a virological (if HCV-RNA was assessed) or biochemical response (if HCV-RNA was not assessed) to interferon monotherapy, 3 mU three times weekly (TIW) for 3-18 months, were randomly assigned to one of three treatment groups. Group A patients were treated with 5 mU interferon TIW for 6 months. Ribavirin (1000-1200 mg daily) was added in those patients HCV-RNA positive at month 3. Group B patients were treated with 3 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. The dose of interferon was increased to 5 mU TIW in those patients HCV-RNA positive at month 3. Group C patients were treated with 5 mU interferon TIW plus ribavirin (1000-1200 mg daily) for 6 months. Serum ALT and HCV-RNA were monitored during and after treatment for a total of 15 months. RESULTS: Seventeen percent of patients in group A became HCV-RNA negative by treatment month 3. Adding ribavirin resulted in one additional patient becoming HCV-RNA negative. However, none of the patients in this group achieved sustained virological response. Twenty-six percent of patients in group B became HCV-RNA negative by treatment month 3. Increasing the dose of interferon from 3 to 5 mU TIW increased virological response to 30%. However, sustained virological response was observed in only 14%. Thirty percent of patients in group C became HCV-RNA negative, but sustained virological response was observed in only 12%. Sustained virological response was found to be significantly greater in patients with a nontype I HCV genotype (p < 0.002) and in patients who had a decline in HCV-RNA titer to a value < 100,000 copies/ml during their previous course of interferon monotherapy (p < 0.0001). None of the 12 sustained responders were African Americans (p < 0.013). CONCLUSIONS: Retreatment of nonresponders with interferon-ribavirin combination therapy results in limited benefit; only 13% of patients achieved sustained virological response. Response was extremely poor in African Americans and those with HCV genotype 1.

Adult↗
PubMed1981

Mechanism of stimulation of natural killer-cell cytotoxicity by interferon and an interferon-inducer in the rat.

The interferon-induced Newcastle disease virus (NDV) was shown to augment cytotoxicity attributable to natural killer (NK) cells in all of the major lymphoid organs of W/Fu rats except the thymus. The levels of interferon isolated from the spleen following NDV inoculation correlated with the increase in splenic cytotoxicity from the same spleen. Spleen-derived interferon was shown to augment splenic cytotoxicity following intravenous inoculation, and to augment spleen cell cytotoxicity in vitro. Three major peaks of interferon type I were found in spleen homogenates corresponding to mol. wt of greater than 100,000, 29-33,000 and 19-23,000. All these fractions stimulated spleen cell cytotoxicity when tested in vitro. The rapid drop in splenic cytotoxicity 24 hr after NDV inoculation was associated with a rapid fall in interferon levels in vivo. The need for the continued presence of interferon for the stimulation of cytotoxicity was demonstrated when spleen cells pretreated with interferon for 4 hr in vitro lost their augmented cytotoxicity upon culturing for a further 20 hr in the absence of interferon. Although splenic cytotoxicity returned to control levels within 24 hr of a single 10(7.3) EID50 dose of NDV, repeated doses of NDV maintained augmented cytotoxicity over a longer period. Spleen cells either taken from rats injected with NDV or pretreated in vitro with interferon showed a two-fold increase in the number of cytotoxic cells bound to W/FuG-1 target cells, with no change in the target binding-cell numbers. However, only the cells pretreated with interferon showed an increase in lytic efficiency.

Animals↗
PubMed1984

The effects of interleukin-1, interleukin-2, alpha-interferon, and gamma-interferon on human B lymphocytes.

The direct effects of interleukin-1 (IL-1), interleukin-2 (IL-2), alpha-interferon, and gamma-interferon on human B cell activation, proliferation, and differentiation have been examined and compared to the effects of B cell growth factor (BCGF) and B cell differentiation factor (BCDF). Human tonsillar B lymphocytes were separated according to cell size into two nonoverlapping and functionally distinct populations. The small fraction was incubated with IL-1, IL-2, alpha-interferon, or gamma-interferon, and subsequent DNA synthesis and immunoglobulin production were measured. None of the factors induced these cells to proliferate or to differentiate. Similarly, the large fraction of B cells was incubated with IL-1, IL-2, alpha-interferon, gamma-interferon, BCGF, or BCDF. BCGF augmented the proliferation, and BCDF augmented the differentiation of the large B cells. In comparison, IL-1, IL-2, alpha-interferon, or gamma-interferon had either a minor effect or no effect on large B cell proliferation and differentiation. Thus, this study suggests that IL-1, IL-2, alpha-interferon, and gamma-interferon are not important direct signals for mature B cell function when present in the absence of other signals.

Adolescent↗
PubMed2003

Effects of exogenous interferon gamma on patients with treatment-resistant chronic rhinosinusitis and dysregulated interferon gamma production: a pilot study.

OBJECTIVE: To evaluate the effects of exogenous interferon gamma treatment in patients with chronic rhinosinusitis and evidence of aberrant production of interferon gamma (IFN-gamma) and its regulatory cytokines. METHODS: Ten patients with treatment-resistant chronic rhinosinusitis (4 males and 6 females) treated with exogenous interferon gamma (50 micro g/m2) were retrospectively evaluated by assessing clinical outcomes compared with clinical and laboratory findings before interferon gamma treatment. RESULTS: Dysregulated IFN-gamma production was suspected to be characterized by (1) decreased interleukin 12 production (n = 1), (2) defects in interleukin 12 receptor signaling (n = 4), (3) intrinsic defects in interleukin 12 (n = 4), and (4) decreased IFN-gamma production. Eight patients had a history of chronic otitis media with positive bacterial cultures of sinus lavage samples. Adverse skin reactions to various antibiotics were reported in 7 patients. Asthma was reported in 4 patients. Along with sinusitis symptoms, these conditions were better controlled in all 9 patients who received exogenous interferon gamma for longer than 3 months. In 1 patient, interferon gamma treatment was discontinued after 3 weeks secondary to "presumed" tremor that was later diagnosed as a tic. Repeated surgical procedures and hospitalizations were reported in 2 patients after interferon gamma treatment secondary to recurrent chronic otitis media/mastoiditis/catheter infection and G-tube leakage. Interferon gamma treatment was discontinued in 1 of these patients because of a concern about neutropenia that occurred after catheter infection. Adverse effects of using exogenous interferon gamma were generally limited to local skin reactions. CONCLUSION: Exogenous interferon gamma may be a therapeutic option in a subset of patients with treatment-resistant chronic rhinosinusitis and evidence of dysregulated IFN-gamma production.

Adolescent↗
PubMed2005

Sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone for HBeAg-positive chronic hepatitis B.

BACKGROUND: Chronic hepatitis B has serious effects on morbidity and mortality. Alfa interferon has been shown to increase the rates of HBeAg-clearance as well as seroconversion to anti-HBe, but response rates are unsatisfactory. Glucocorticosteroid pretreatment may increase the response to alfa interferon. OBJECTIVES: The objectives were to assess the effects of the sequential combination of glucocorticosteroids and alfa interferon versus alfa interferon alone in hepatitis B 'e' antigen positive chronic hepatitis B on mortality, virological response, biochemical response, liver histology, quality of life, and adverse events. SEARCH STRATEGY: Eligible trials were identified through searches of The Cochrane Hepato-Biliary Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (Excerpta Medica Database) (1980 to May 2005), BIOSIS (1969 to May 2005), and reference lists of relevant articles. Further trials were sought through correspondence with authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing identical alfa interferon treatment regimens with and without glucocorticosteroid pretreatment for hepatitis B 'e' antigen positive chronic hepatitis. We included trials irrespective blinding, publication status, or language. DATA COLLECTION AND ANALYSIS: Three authors selected the trials independently and one extracted the data, which were then validated. We performed assessments of the outcome measures at the end of treatment and at six months and at maximal follow-up after the end of treatment with alfa interferon. MAIN RESULTS: We included a total of 13 randomised trials with 790 patients. Loss of hepatitis B 'e' antigen (OR 1.41, 95% confidence interval 1.03 to 1.92, P = 0.03) and hepatitis B virus DNA (OR = 1.51, 95% confidence interval 1.12 to 2.05, P = 0.008) were significantly more frequent among patients treated with the sequential combination of glucocorticosteroids and alfa interferon than among patients treated with alfa interferon alone. Glucocorticosteroid pretreatment did not significantly influence seroconversion from hepatitis B 'e' antigen to antibodies to hepatitis B 'e' antigen, loss of hepatitis B surface antigen, normalisation of alanine aminotransferase/aspartate aminotransferase activities, and severity of adverse events. Glucocorticosteroid pretreatment did not significantly affect mortality and adverse events. The effect of glucocorticosteroid pretreatment on liver histology and quality of life could not be assessed due to insufficient data. AUTHORS' CONCLUSIONS: Pretreatment with glucocorticosteroids before treatment with alfa interferon in patients with hepatitis B 'e' antigen positive chronic hepatitis B may be more effective than treatment with alfa interferon alone with regard to loss of hepatitis B 'e' antigen and hepatitis B virus DNA, but evidence for effect on clinical outcomes is lacking.

Antiviral Agents↗
PubMed1990

Interferon selectively inhibits the expression of mitochondrial genes: a novel pathway for interferon-mediated responses.

As an approach to identifying genes involved in physiological actions of interferons we used differential probes to screen a cDNA library from mouse L-929 cells treated with interferon alpha/beta. We identified two negatively regulated mRNA species which have been examined by analysis of the corresponding mRNAs and by DNA sequencing. Comparison with the GenBank database showed that these cDNA clones corresponded to mitochondrially encoded genes for cytochrome b and subunit I of cytochrome c oxidase. A further cDNA encompassing three mitochondrial genes was used as a probe to show that a third mRNA, NADH dehydrogenase subunit 5, was also down-regulated by interferon while a fourth, NADH dehydrogenase subunit 6, was unaffected. Expression of cytochrome b was also inhibited in mouse NIH 3T3 cells treated with interferon alpha/beta and in human Daudi lymphoblastoid cells treated with interferon alpha. The ability of interferon to reduce mitochondrial mRNA levels could be blocked by cycloheximide suggesting that these effects are mediated by an interferon-responsive nuclear gene which encodes a product capable of regulating mitochondrial gene expression. Analysis of proteins synthesized in the presence of emetine, a specific inhibitor of cytoplasmic translation, showed that the synthesis of several mitochondrial translation products, including cytochrome b, was reduced after treatment with interferon. Our results reveal a novel effect of interferon on cellular physiology which could have important consequences for understanding the effects of interferons as well as suggesting new mechanisms for the regulation of mitochondrial biogenesis and function.

Animals↗
PubMed1980

Abnormal behavior of interferon-induced enzymatic activities in an interferon-resistant cell line.

Interferon induces two double-stranded RNA-dependent enzymatic activities: an oligoisoadenylate synthetase that converts ATP to ppp(A2'p)n5'A, and a protein phosphokinase. We have explored the level and inducibility of these two enzymes in a human cell line (HEC-1) totally insensitive to both the antiviral and the anticellular actions of interferon. The activities of both enzymes are high in untreated cells and only minor changes occur after treatment with interferon, even at high concentrations. Interferon-treated HEC-1 cells do not contain an inhibitor of the oligoisoadenylate synthetase activity. The products of this HEC-1 oligoisoadenylate synthetase consist mainly of dimers, trimers, and tetramers as found in other cell lines after interferon treatment. The synthetase level is unaffected by treating the cells with anti-interferon antiserum, indicating that the results cannot be explained by a spontaneous low production of interferon by these cells. Furthermore, virus multiplication is not inhibited, even after treatment with interferon. These observations suggest that either the two enzymatic activities do not suffice for the establishment of an antiviral state in vivo or that a regulatory control mechanism, lost in these cells and common for both enzymes, is required for the expression of the antiviral action of interferon. This might explain both the constitutivity of the two enzymes and the interferon resistance observed.

2',5'-Oligoadenylate Synthetase↗
PubMed1978

Interferon action III. The rate of primary transcription of vesicular stomatitis virus is inhibited by interferon action.

Transcription of vesicular stomatitis virus (VSV) in Vero cells was confined to the synthesis of parentally-derived mRNA (primary transcription) by the use of cycloheximide and/or a ts mutant, G41(IV), at a non-permissive temperature (40 degrees C). More transcripts accumulated in the presence of cycloheximide than in its absence. This so-called "cycloheximide effect" results from higher rates of virus transcription sustained for longer periods of time. The rate of VSV transcription initially increases linearly for 1 to 2 h after injection. Interferon reduces this rate (congruent to fourfold with 50 units/ml interferon) irrespective of the presence or absence of cycloheximide. The VSV mRNA transcripts synthesized in mock- or interferon-treated cells were equal in size and had an equivalent half-life of 17 h at 40 degrees C. It seems likely that once transcription is initiated in interferon-treated cells, it is completed successfully. Since interferon reduces the rate of early VSV primary transcript synthesis to below that achieved in the presence of cycloheximide, we conclude that interferon has an effect on transcription beyond that attributable solely to protein synthesis inhibition. We postulate that interferon decreases the probabiltiy of initiating virus transcription. Virus mRNA escaping this facet of interferon action may then encounter other facets such as post-transcriptional modification and/or inhibition of translation. However, the mandatory sequence of primary transcription leads to primary translation for negative-strand viruses like VSV dictates that the overall inhibitory effect of interferon on translation would derive in part from this prior inhibition of transcription. Thus, to apply the term "primary effect" to one particular facet of interferon action may not always be meaningful.

Cycloheximide↗
PubMed1979

Protection of mice against infection with wild-type Mengo virus and an interferon sensitive mutant (IS-1) by polynucleotides and interferons.

Single-stranded polynucleotide preparations [tRNA, poly(rI) plus poly(ho5C)-copolymer] which protect mice against picornavirus infections without inducing interferon, protected mice equally against infection with an interferon-sensitive mutant (IS-1) of Mengo virus and with wild-type virus (IS+). Poly(rI) . poly(rC), and mouse macrophage interferon [i.e. serum from mice treated with poly(rI) . poly(rC)] protected mice equally against infections with the two viruses, but fibroblast interferon protected better against infection with the interferon-sensitive mutant than with the wild-type virus. These and other results indicate that: Mengo virus had a genetic locus affecting sensitivity to fibroblast but not macrophage interferon; these two types of interferon have different mechanisms of action against Mengo virus infections in mice; Mengo virus genes controlling sensitivity to fibroblast interferon may modulate disease since infection in vivo induces only fibroblast interferon; the antiviral activity of the single-stranded polynucleotides is unlikely to be mediated by induction of either macrophage or fibroblast interferon.

Animals↗
PubMed1991

Abrogation of interferon-induced resistance to interferon-activated major histocompatibility complex-unrestricted killers by treatment of a melanoma cell line with 5-fluorouracil.

Advanced cancer responds clinically to combined therapy with recombinant interferon-alpha and 5-fluorouracil. Although the two agents may interact in the biosynthetic pathway for thymidine, we investigated, as an alternative mechanism, the regulation of susceptibility of the A375 human melanoma to natural killers activated by interferon. A375 were preincubated with 5-fluorouracil, interferon, or both sequentially prior to assay as targets for cell-mediated killing. Pretreatment of A375 with interferon decreased apparent lytic efficiency. 5-Fluorouracil alone increased the susceptibility of A375 to killing. Pretreatment of targets with 5-fluorouracil abrogated the resistance normally induced by interferon pretreatment. Thus, 5-fluorouracil modulates certain immunoregulatory effects of interferon-alpha. Thymidine does not block the effect of 5-fluorouracil. While fluorodeoxyuridine is relatively ineffective in this system, fluorouridine is more effective than 5-fluorouracil in abrogating the effect of interferon. These data suggest important interactions of 5-fluorouracil and interferon in pathways for protein synthesis. It is known that interferon both increases the activity of natural killers and increases resistance of tumors to natural killers. We have shown that 5-fluorouracil, by blocking the resistance, may allow the augmented natural killing to be effective. This observation provides an alternate hypothesis for the clinical activity of 5-fluorouracil and interferon in combination.

Adult↗
PubMed1981

The transformation of adult but not newborn human lymphocytes by Epstein Barr virus and phytohemagglutinin is inhibited by interferon: the early suppression by T cells of Epstein Barr infection is mediated by interferon.

In a previous study, it was demonstrated that T cells from adult individuals were able to suppress the transformation of B cells after infection by EBV. In this paper, it is shown that this suppression is mediated by interferon. Thus, the suppression is abrogated by anti-interferon serum and mimicked by human leukocyte interferon. Furthermore, the interferon is released in response to the virus-infected B cell, not the virus alone. The relevance of these results to previous clinical evidence, indicating a role for interferon in recovery from EBV infection, is discussed. Interferon will also suppress the transformation of adult B lymphocytes by the mitogen phytohemagglutinin (PHA). However, interferon at concentrations 2 to 3 orders of magnitude higher was unable to suppress the transformation of neonatal B lymphocytes by either EBV or PHA. These experiments suggest that EBV and PHA induced transformation share a common interferon sensitive step. Lastly, the resistance of newborn lymphocytes to the protective effect of interferon may be an important consideration in the application of interferon as an antiviral or anti-tumor agent.

B-Lymphocytes↗
PubMed1984

Interferons as modulators of human monocyte-macrophage differentiation. I. Interferon-gamma increases HLA-DR expression and inhibits phagocytosis of zymosan.

The development of HLA-DR (Ia) expression in the presence and absence of interferon-gamma was monitored in monocyte-macrophage cultures. Overnight incubation with doses as low as 5 U/ml gave elevated values for Ia expression and the maximum increase was obtained with 200 U/ml. In contrast interferon-alpha had only a slight effect on the expression of Ia at doses as high as 2000 U/ml. The increase seen at 24 hr was maintained during the first 2 days of culture. The interferon-gamma-treated cells expressed four to five times more Ia than fresh monocytes. During the same time, monocytes cultured in the absence of interferon expressed approximately two times the amount of fresh monocytes. When the surface density of Ia was calculated, the interferon-gamma-treated monocytes expressed twice that of the untreated cells. Major changes in morphology and size occurred between days 3 and 4 of monocyte to macrophage development. Consequently a rapid increase in Ia expression took place; however, when the surface density was calculated this value increased only slightly when the monocytes matured to macrophages. The interferon-gamma-treated cells continued to express more total Ia as well as having increased surface density of this antigen. Interferon-gamma was also added to monocyte-macrophages several days after culture initiation (days 3, 4, and 5). Despite being in different stages of maturation, the cells responded to the interferon with increased Ia expression and surface density. The phagocytic activity of opsonized zymosans was also monitored. In contrast to Ia expression, this activity was downregulated by interferon-gamma, and the lower levels of phagocytosis were maintained through the 7 days of observation. Thus, interferon-gamma appears to change the differentiation pathway of the monocyte. The signal stimulates an increased level of Ia that may assist in the initiation of immune responses, and at the same time downregulates the scavenger role of removing opsonized particles. Once the monocyte has received this specific signal it continues to develop in a pathway different from that of the nontreated monocytes.

Cell Differentiation↗