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PubMed1997

Clinical and biological effects of gamma interferon and the combination of gamma interferon and interleukin-2 after autologous bone marrow transplantation.

Interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) have shown synergistic immunomodulatory and anti-tumor effects in preclinical studies. The present study was designed to assess the effects of the combination of these cytokines after autologous bone marrow transplantation (ABMT). Ten patients received rIFN-gamma alone and 13 patients the combination of rIFN-gamma + rIL-2. Patients received transplants because of lymphoma (10 patients), acute leukemia (3 patients) or solid tumors (10 patients). Immunotherapy was started at a median of 67 days after ABMT. All patients received either 5 x 10(6) (8 pts) or 10 x 10(6) IU/m2 (16 pts) rIFN-gamma by subcutaneous injection 3 times weekly for 14 weeks. rIL-2 therapy consisted of 5 cycles of continuous intravenous infusion of 12 x 10(6) IU/m2/day starting 1 week after administration of rIFN-gamma. In the rIFN-gamma group, toxicity was mild and some biological changes were seen (NK/LAK activation, increase of phagocytosis and of NBT reduction). The combination of rIFN-gamma with rIL-2 did not increase the usual rIL-2 toxicity. NK/LAK cytotoxicity was strongly activated after the first cycle of rIL-2 and was maintained until the end of therapy. Granulocyte chemotaxis was defective after cycle 1 but recovered thereafter. We conclude that the administration of rIFN-gamma + rIL-2 is feasible after ABMT. Our data suggest that the combination may have prolonged the immunologic activation provided by rIL-2 and some improvement of the deleterious effects of rIL-2 on granulocyte functions was achieved. Controlled studies are warranted to assess the impact of this strategy on biological response and patient outcome.

Adjuvants, Immunologic↗
PubMed1998

Interferon regulatory factor-1 gene abnormality and loss of growth inhibitory effect of interferon-alpha in human hepatoma cell lines.

The effect of IFN-alpha on the growth of 5 hepatoma cell lines and a normal liver-derived cell line were examined. IFN dose-dependently inhibited the growth of cell lines except for HLE and PLC/PRF/5 in which the inhibition only occurred at a high concentration over 10,000 IU/ml. IFN-alpha induced the G1 arrest of these cells according to upregulation of p21WAF-1 expression, which is induced in PLC/PRF/5 and HLE only at a high IFN concentration. The receptor for IFN-alpha was well expressed in all the cell lines. DNA rearrangement of IRF-1 was detected in HLE and PLC/PRF/5 by Southern blotting, while IRF-2 gene was preserved. IFN-induced gene expressions were compared between HCC-T, HCC-M and PLC/PRF/5. RT-PCR demonstrated that the full-length IRF-1 and -2 mRNA was transcribed in all cell lines, but the mRNA amount of former gene in PLC/PRF/5 was less than that in HCC-T and HCC-M, about 1/10 by competitive RT-PCR. The sequence analysis of IRF-1 cDNA was performed and the full-length mRNA transcription was reconfirmed in PLC/PRF/5, but no significant point mutation was detected. These results suggest that IFN-alpha inhibits hepatoma growth by increasing p21WAF-1 expression only when the IRF-1 gene is preserved normally.

Base Sequence↗
PubMed2003

Induction of interferon-inducible protein-10 and monokine induced by interferon-gamma from human endothelial cells infected with Influenza A virus.

Primary human umbilical vein endothelial cells (HUVECs) were infected with Influenza virus A/Aichi/2/68 (H3N2) in order to determine the role of endothelial cells in mediating inflammation induced upon virus infection. Structural proteins of the virus and mRNA of the M2 protein were detected in the infected cells, indicating that virus infection had occurred in HUVECs. The Influenza A virus-infected HUVECs showed elevated levels of gene expression of interferon (IFN)-inducible protein (IP)-10 and monokine induced by IFN-gamma (Mig), while heat-, formalin- and diethyl ether-inactivated viruses did not enhance the IP-10 and Mig gene expression. The results thus indicate that infection of live Influenza A virus is responsible for elevation of IP-10 and Mig gene expression. The elevation of IP-10 and Mig gene expression in infected HUVECs was not accompanied by the elevation of IFN-gamma gene expression, indicating that the elevation of IP-10 and Mig gene expression was independent of the IFN-gamma pathway.

Cells, Cultured↗
PubMed2002

Interferon-gamma brings additive anti-viral environment when combined with interferon-alpha in patients with chronic hepatitis C.

T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-gamma injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-alpha 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-gamma 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. beta2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-alpha and increased more with IFN-gamma. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-alpha but increased after IFN-alpha was replaced by IFN-gamma. IL-10 was not changed either with IFN-alpha or gamma. Productions of IL-2, IFN-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells did not change by IFN-alpha therapy, however, they were enhanced at the end of IFN-gamma therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-gamma in patients with chronic hepatitis C. Combination of these two IFNs should be explored.

Journal Article↗
PubMed2002

Interferon beta induction/interferon alpha therapy in patients with interferon-resistant chronic hepatitis C.

The treatment of chronic hepatitis C with a standard regimen of therapy with interferon (IFN) alpha for 6 months results in a sustained response (SR) in a minority of patients with high levels of HCV-RNA. The aim of this study was to assess whether a high dose of IFN and IFN beta induction/IFN alpha therapy increase efficacy, and to identify the determinants or predictive factors of SR in patients with IFN resistant chronic hepatitis C. In 99 patients with high levels of HCV-RNA (>1 Meq/ml), we compared the efficacy of IFN beta induction/IFN alpha therapy (n=50) and IFN alpha monotherapy (n=49). HCV-RNA clearence was observed in 22 patients (44%) in IFN beta induction/IFN alpha group and 11 (22.4%) in IFN alpha monotherapy group at 7 days after the start of treatment, there were significant difference between these two groups (P=0.0327); in 26 (52%) and 13 (26.5%) at the end of treatment, there were significant difference between these two groups (P=0.0134); in 9 (18%) and 3 (6.1%) at 6 months after the end of treatment, there was no difference between these two groups (P=0.1212), respectively. SR was observed in 9 (18%) and non-response in 41 (82%) with the IFN beta induction/IFN alpha therapy, and in 3 (6.1%) and 46 (93.9%) with IFN alpha monotherapy, respectively. IFN beta induction/IFN alpha therapy was better than IFN alpha monotherapy by HCV-RNA clearance at 7 days after the start of treatment and at the end of treatment, but there was no significant difference between these two groups at 6 months after the end of treatment. IFN beta induction/IFN alpha therapy was superior to IFN alpha monotherapy in the treatment of chronic hepatitis C, and this therapy may be recommended for patients with high levels of HCV-RNA of chronic hepatitis C.

Journal Article↗
PubMed2003

Hepatic expression of type I interferon receptor for predicting response to interferon therapy in chronic hepatitis C patients: a comparison of immunohistochemical method vs. competitive polymerase chain reaction assay.

The focus of this study is to determine both mRNA and protein expression levels of the type I interferon (IFN) receptor subunits, IFNalpha receptor (IFNAR1) and IFNalpha/beta receptor (IFNAR2), in the liver, and to assess which quantification method is most useful in predicting response to IFN in chronic hepatitis C patients. Liver biopsy specimens from 41 chronic hepatitis C patients subsequently treated with IFN were immunostained with IFNAR1 and IFNAR2 antibodies, and also analyzed for both receptor subunit mRNA levels, using competitive polymerase chain reaction. Immunostaining of IFNAR1 and IFNAR2 was observed in the cell membrane and cytoplasm of hepatocytes in all liver specimens. Hepatic expression of IFNAR1 (r=0.45, P=0.012) or IFNAR2 mRNA (r=0.46, P=0.009) was weakly correlated with their protein expression in hepatocytes. The labeling indexes of IFNAR1 (136.7+/-94.1 vs. 77.4+/-76.8, P=0.032) and IFNAR2 (153.1+/-80.2 vs. 87.2+/-75.5, P=0.011) in liver specimens were significantly higher in sustained virologic responders (n=17) than in non-sustained virologic responders (n=24), while mRNA levels of either receptor subunit did not differ between response groups. These results suggest that protein expression of the type I IFN receptor in liver is a more useful measure than its mRNA expression in predicting response to IFN in chronic hepatitis C patients.

Journal Article↗
PubMed2003

A randomised, open label, controlled trial on the effect of interferon plus amantadine compared with interferon alone for treatment of chronic hepatitis C.

BACKGROUND: Combination of the antiviral drug amantadine with interferon (IFN) may be more effective than IFN monotherapy for treatment of chronic hepatitis C. METHODS: We randomised 93 patients with chronic hepatitis C to IFNIFN 6 MU 3 times/week for 24 weeks, followed by IFN 3 MU 3 times/week for further 24 weeks given in combination with amantadine 100 mg t.i.d. (regimen A, n=48) or as monotherapy (regimen B, n=45). Control liver biopsies were obtained 6 months post treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum ALT levels (35% for regimen A, and 44% for regimen B) as measured by intention to treat criteria. Sustained biochemical response at 6 months post treatment was 15 and 20%, and sustained virological response was 10 and 20% for regimen A and B, respectively. The effect on liver histology was also similar: the inflammatory components of the Knodell score decreased by 1.3+/-0.6 points for regimen A and by 1.6+/-0.6 for regimen B, and score for fibrosis remained unchanged with both regimens. CONCLUSIONS: Combination of IFN therapy with amantadine does not enhance the effect of IFN as shown by biochemical, virological and histological criteria.

Journal Article↗
PubMed2000

Early expression of interferon-gamma inducible protein 10 and monokine induced by interferon-gamma in cardiac allografts is mediated by CD8+ T cells.

BACKGROUND: Our goal was to test the intragraft mRNA expression and production of two chemokines that are potent chemoattractants for antigen-primed T cells, interferon-gamma inducible protein 10 (IP-10) and monokine-induced by IFN-gamma, (Mig), in allogeneic heart grafts. METHODS: Syngeneic or allogeneic A/J (H-2a) hearts were heterotopically transplanted to wild-type, CD4-/-, CD8alpha-/-, or IFN-gamma-/- C57BL/6 (H-2b) recipients. To test expression of IP-10 and Mig, grafts were removed 1-8 days posttransplant for RNA isolation and Northern blot analysis. To test the potential recipient leukocyte populations mediating intraallograft expression of IP-10 and Mig, recipients were treated with anti-NK 1.1, anti-CD4, and/or anti-CD8 monoclonal antibodies before transplantation. RESULTS: Allogeneic heart grafts transplanted to wild-type, but not IFN-gamma-/-, recipients expressed IP-10 and Mig at day +2 posttransplant that increased thereafter until rejection was completed. Expression of IP-10 and Mig in isografts was low or undetectable. Cardiac allografts from CD8+ T cell depleted, but not NK cell or CD4+ T cell depleted, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. Similarly, cardiac allografts from CD8-/-, but not CD4-/-, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. CONCLUSIONS: Early intraallograft expression of Mig and IP-10 during primary rejection of cardiac allografts is dependent on the activities of recipient CD8+ T cells.

Animals↗
PubMed1971

Effect of Interferon and Interferon Inducers on Infections with a Nonviral Intracellular Microorganism, Rickettsia akari.

The effect of mouse interferon (IF) on the multiplication of Rickettsia akari in homologous (L-929) cell cultures and the effect of IF inducers on R. akari infection in mice were investigated. There was a reduction in the proportion of cells containing rickettsiae in IF-treated cultures and in the yield of rickettsiae from these cultures, as compared with those from infected cultures without IF. Trypsin treatment and heating for 1 hr at 65 C destroyed this antirickettsial activity of the IF preparation, whereas ultracentrifugation (105,000 x g for 90 min) and acidification at pH 2.0 did not affect it. There was no evidence that mouse IF inactivated R. akari directly, nor did it have an inhibitory effect on multiplication of R. akari in heterologous chick embryo cell or monkey kidney cell cultures. Susceptibility of R. akari to the action of IF was about 16 times less than that of Chlamydia trachomatis and 256 times less than the susceptibility of vesicular stomatitis virus. Mice were not protected from infection with R. akari by intraperitoneal injection with IF inducers, Newcastle disease virus (10(8.3) plaque-forming units/0.2 ml) or polyriboinosinic acid-polyribocytidylic acid complex (poly I:C, 200 mug/0.2 ml), within 24 hr before or 24 hr after intraperitoneal challenge. The yields of R. akari harvested from the spleens, livers, and peritoneal washings of infected mice treated with IF inducers were similar to those of infected control mice. Titers of IF in peritoneal washings of treated mice, taken 6 hr after administration of Newcastle disease virus or 9 hr after injection of poly I:C, were 1,024 or 320 units/ml, respectively.

Journal Article↗
PubMed1971

Effect of Interferon and Interferon Inducers on Infections with a Nonviral Intracellular Microorganism, Chlamydia trachomatis.

The effect of mouse interferon (IF) on the multiplication of Chlamydia trachomatis (strain MRC-1/G) in homologous (L-929) cell cultures and the effect of the IF inducers Newcastle disease virus (NDV) and polyriboinosinic acid-polyribocytidylic acid complex (poly I:C) on the experimental infection of mice with aerosolized C. trachomatis (strain MoPn) were investigated. Treatment of infected cell cultures with IF reduced the number of cells containing chlamydial inclusions and depressed the yield of chlamydiae as determined by titrations for infectivity. Growth of chlamydiae was reduced when cultures were exposed to IF 6 or 18 hr before infection, and slight reduction of the yield was also detectable in cell cultures treated with IF at early intervals (0 or 4 hr) after chlamydial infection. No effect of IF on penetration of chlamydiae into mouse cells was observed, whether phagocytic cells from peritoneal washings or L-929 cells were used, indicating that the inhibitory effect of IF occurs after chlamydiae enter the host cell. Additional evidence was obtained that a significant effect of IF occurs at an early stage in maturation of the intracellular chlamydiae. In mice exposed repeatedly to NDV aerosols and challenged with aerosolized MoPn 8 hr after the first exposure to NDV, mortality was delayed by 2 to 3 days and lung consolidation was slightly reduced at 3 days after infection. Yields of chlamydiae from lung pools of NDV-treated mice, taken at 3, 6, and 9 days after challenge, were not significantly different from those of controls. Similar results were obtained when mice were challenged with MoPn 8 hr after intranasal injection with 100 mug of poly I:C or 24 hr after intravenous injection with 200 mug of poly I:C. In contrast, administration of 0.2 ml of NDV (10(8.3) plaque-forming units) intravenously 10 hr before or 24 hr after challenge with MoPn accelerated mortality of mice by 2 to 3 days. In all experiments, detectable levels of IF in sera or 20% lung suspensions were found only up to 48 to 72 hr after exposure of mice to IF inducers.

Journal Article↗
PubMed2000

CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma-inducible protein 10 and monokine induced by interferon gamma.

CXC chemokine receptor 3 (CXCR3), which is known to be expressed predominately on memory and activated T lymphocytes, is a receptor for both interferon gamma (IFN-gamma)-inducible protein 10 (gamma IP-10) and monokine induced by IFN-gamma (Mig). We report the novel finding that CXCR3 is also expressed on CD34(+) hematopoietic progenitors from human cord blood stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) but not on freshly isolated CD34(+) progenitors. Freshly isolated CD34(+) progenitors expressed low levels of CXCR3 messenger RNA, but this expression was highly up-regulated by GM-CSF, as indicated by a real-time quantitative reverse transcriptase-polymerase chain reaction technique. gamma IP-10 and Mig induced chemotaxis of GM-CSF-stimulated CD34(+) progenitors by means of CXCR3, since an anti-CXCR3 monoclonal antibody (mAb) was found to block gamma IP-10-induced and Mig-induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 mAb blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment for the physiologic and pathophysiologic events of differentiation of CD34(+) hematopoietic progenitors into lymphoid and myeloid stem cells, subsequently immune and inflammatory cells. These processes include transmigration, relocation, differentiation, and maturation of CD34(+) hematopoietic progenitors. (Blood. 2000;96:1230-1238)

Antigens, CD34↗
PubMed1999

Differential induction of monocyte chemotactic protein-3 in mononuclear leukocytes and fibroblasts by interferon-alpha/beta and interferon-gamma reveals MCP-3 heterogeneity.

Monocyte chemotactic protein-3 (MCP-3) is a pluripotent CC chemokine, attracting most leukocytic cell types. With the use of a sensitive and specific ELISA, MCP-3 was found to be inducible in fibroblasts and peripheral blood mononuclear cells (PBMC) by cytokines and cytokine inducers. MCP-3 production levels (1-10 ng/ml) were tenfold lower compared to those of MCP-1. In diploid fibroblasts, synergistic induction of MCP-3, but not of MCP-1, mRNA and protein was observed by combined treatment with IL-1beta and IFN-gamma. In PBMC, IFN-alpha and IFN-beta (but not IFN-gamma), as well as measles virus and double-stranded RNA, were potent inducers of MCP-3, which suggests a role for this chemokine in an early stage of viral infections. In contrast, endotoxin failed to induce MCP-3 production in fibroblasts and PBMC. Purification of MCP-3 from PBMC revealed biochemical heterogeneity. In monocyte chemotaxis and calcium mobilization assays, pure 11-kDa MCP-3 from PBMC showed similar potencies as MCP-3 from tumor cells. It was concluded that the induction of MCP-3 by IFN is regulated differently in fibroblasts and PBMC. In view of the multiple target cells for MCP-3, local and strictly regulated chemokine production might be important to conduct selectively the immune response in infection or inflammation.

Cells, Cultured↗
PubMed2000

In vivo subcellular target compartments of interferon-gamma and interferon-gamma receptor (alpha- and beta-chains) in mouse liver.

IFN-gamma displays several effects on different tissues via its specific cell surface receptor (IFN-gammaR). In order to identify the target compartments of IFN-gamma and IFN-gammaR (alpha and beta-chains), we used a quantitative immunogold approach. In physiological conditions, IFN-gamma and IFN-gammaR immunoreactivities were detected in the plasma membrane, in the endoplasmic reticulum area, in the mitochondria and in the nucleus. After a single IFN-gamma injection, we observed, in a quantitative manner, an increase of signal density without modification of the subcellular distribution of IFN-gamma and IFN-gammaR subunits.

Animals↗
PubMed2002

Synergy of type I interferon-A6 and interferon-B naked DNA immunotherapy for cytomegalovirus infection.

Delivery of type I IFN transgenes by naked DNA immunization can protect against cytomegalovirus infection and myocarditis. Here, we investigate IFN transgene expression, antiviral efficacy, and immunomodulation of myocarditis using various treatment regimes in a mouse CMV model. In vivo expression of the IFN transgene was observed in the sera for 35 days post-DNA inoculation. Prophylactic IFN-A6 and IFN-B DNA treatment for 14 days prior to murine cytomegalovirus (MCMV) infection was more efficacious in significantly reducing viral titres, than 2 days prior to or 2 days post-virus infection. Similarly, IFN-A6 DNA treatment commencing 14 days prior to virus infection was superior in suppressing both acute and chronic myocarditis. Furthermore, reduction of autoantibody titres was more pronounced when IFN was administered 14 days prior to viral infection. Combinational IFN gene therapy was assessed for synergy between IFN subtypes. Combination treatment with either IFN-A6/A9 or IFN-A6/B greatly reduced spleen viral titres while IFN-A6/B and IFN-A9/B reduced virus replication in the liver. Only IFN-A6/A9 and IFN-A9/B reduced acute viral myocarditis, whereas IFNA6/B treatment was most efficacious for autoimmune chronic myocarditis. Finally, treatment with IFN-A6 DNA 2 weeks post-MCMV infection proved effective at inhibiting the development of chronic autoimmune myocarditis. These findings suggest that immunomodulation of both antiviral and autoimmune responses by IFN DNA immunization may be an avenue for improved viral immunotherapy.

Acute Disease↗