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Davtyan TK, Poghosyan DA, Sukiasyan AG, Grant MD. The anti-idiotypic antibody 1F7 stimulates monocyte interleukin-10 production and induces endotoxin tolerance. JOURNAL OF INFLAMMATION-LONDON 2013; 10:14. [PMID: 23561395 PMCID: PMC3635981 DOI: 10.1186/1476-9255-10-14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 04/03/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pathogens that establish chronic infection elicit immune responses with suppressive cytokines dominating over pro-inflammatory cytokines. Chronic hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection and simian immunodeficiency virus (SIV) infection are associated with high levels of antiviral antibodies expressing a common idiotype specifically recognized by the 1F7 monoclonal antibody (mAb). The 1F7 mAb is a murine IgMκ antibody raised against immunoglobulin pooled from the plasma of multiple HIV-infected individuals. In this study, we investigated direct effects of the 1F7 mAb itself on peripheral blood mononuclear cells (PBMC). METHODS Isolated monocytes or PBMC from healthy controls were incubated with the 1F7 mAb or IgMκ mAb control. Cytokine production was measured in cell culture supernatants by ELISA and cells producing interleukin-10 (IL-10) were identified by subset depletion and intracellular flow cytometry. Endotoxin tolerance was assessed by exposing monocytes to lipopolysaccharide (LPS) following 1F7 mAb or IgMκ mAb control pre-treatment and comparing tumor necrosis factor (TNF)-α levels in cell culture supernatants. RESULTS The 1F7 mAb stimulated monocytes and CD36+ lymphocytes to produce IL-10 in a time and dose-dependent manner. Treatment of monocytes with 1F7 mAb also reduced their subsequent responsiveness to LPS stimulation. CONCLUSIONS Induction of antibodies expressing the 1F7 idiotype by chronic pathogens may facilitate IL-10 production and progression to chronic infection. Direct effects of IL-10 from human monocytes stimulated by 1F7-like antibodies, followed by monocyte transition to an alternatively activated phenotype illustrated by endotoxin tolerance, are two complementary features favouring a tolerogenic or non-responsive immunological environment.
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Affiliation(s)
- Tigran K Davtyan
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St, John's, NL, Canada.
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Kobayashi T, Nakatsuka K, Shimizu M, Tamura H, Shinya E, Atsukawa M, Harimoto H, Takahashi H, Sakamoto C. Ribavirin modulates the conversion of human CD4(+) CD25(-) T cell to CD4(+) CD25(+) FOXP3(+) T cell via suppressing interleukin-10-producing regulatory T cell. Immunology 2012; 137:259-70. [PMID: 22891772 DOI: 10.1111/imm.12005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Because regulatory T (Treg) cells play an important role in modulating the immune system response against both endogenous and exogenous antigens, their control is critical to establish immunotherapy against autoimmune disorders, chronic viral infections and tumours. Ribavirin (RBV), an antiviral reagent used with interferon, is known to polarize the T helper (Th) 1/2 cell balance toward Th1 cells. Although the immunoregulatory mechanisms of RBV are not fully understood, it has been expected that RBV would affect T reg cells to modulate the Th1/2 cell balance. To confirm this hypothesis, we investigated whether RBV modulates the inhibitory activity of human peripheral CD4(+) CD25(+) CD127(-) T cells in vitro. CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV lose their ability to inhibit the proliferation of CD4(+) CD25(-) T cells. Expression of Forkhead box P3 (FOXP3) in CD4(+) CD25(-) T cells was down-modulated when they were incubated with CD4(+) CD25(+) CD127(-) T cells pre-incubated with RBV without down-modulating CD45RO on their surface. In addition, transwell assays and cytokine-neutralizing assays revealed that this effect depended mainly on the inhibition of interleukin-10 (IL-10) produced from CD4(+) CD25(+) CD127(-) T cells. These results indicated that RBV might inhibit the conversion of CD4(+) CD25(-) FOXP3(-) naive T cells into CD4(+) CD25(+) FOXP3(+) adaptive Treg cells by down-modulating the IL-10-producing Treg 1 cells to prevent these effector T cells from entering anergy and to maintain Th1 cell activity. Taken together, our findings suggest that RBV would be useful for both elimination of long-term viral infections such as hepatitis C virus infection and for up-regulation of tumour-specific cellular immune responses to prevent carcinogenesis, especially hepatocellular carcinoma.
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Affiliation(s)
- Tamaki Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Shaker OG, Sadik NAH. Polymorphisms in interleukin-10 and interleukin-28B genes in Egyptian patients with chronic hepatitis C virus genotype 4 and their effect on the response to pegylated interferon/ribavirin-therapy. J Gastroenterol Hepatol 2012; 27:1842-9. [PMID: 23020144 DOI: 10.1111/j.1440-1746.2012.07273.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Recently, it has been suggested that single nucleotide polymorphisms (SNPs) in some cytokine genes may influence the production of the associated cytokines that affect the host immune response to pegylated interferon-α (Peg-IFN-α) with ribavirin (RBV) in hepatitis C virus (HCV) patients. The aim of the present study was to investigate the possible role of the SNPs of IL-10 and Il-28B and their serum levels in predicting the response to treatment of HCV-4. METHODS Egyptian patients were treated with Peg-IFN-α/RBV. A total of 100 HCV genotype 4-infected patients and 80 healthy control subjects were included in the present study. SNPs in the IL-10 (-592 A/C and -819 T/C) and IL-28B (rs8099917 T/G and rs12979860 C/T) genes and their serum levels were assessed. The IL-10-592-CC, IL-28-rs8099917-TT and IL-28-rs12979860-CC genotypes were significantly higher in responders than in non-responders. RESULTS Interestingly, the serum levels of IL-10 were significantly increased; in contrast, the serum levels of Il-28B were significantly decreased in HCV patients compared with normal patients. Polymorphisms in IL-28B are more sensitive (P < 0.001) than those in IL-10-592 (P = 0.03). However, the serum level of IL-10 is higher than that of IL-28, and this difference can serve as a prognostic marker using a receiver operator characteristic (ROC) analysis. CONCLUSIONS It can be concluded that SNPs in IL-28B and the serum levels of Il-10 and IL-28 may be promising predictors for HCV therapy.
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Affiliation(s)
- Olfat G Shaker
- Medical Biochemistry and Molecular Biology Department, Cairo, Egypt
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Sofian M, Aghakhani A, Farazi AA, Banifazl M, Eslamifar A, Rashidi N, Khadem Sadegh A, Ramezani A. Serum profile of T helper 1 and T helper 2 cytokines in hepatitis C virus infected patients. HEPATITIS MONTHLY 2012; 12:e6156. [PMID: 23423691 PMCID: PMC3575547 DOI: 10.5812/hepatmon.6156] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 06/12/2012] [Accepted: 06/15/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND T-helper (Th) lymphocyte cytokine production may be important in the immune pathogenesis of hepatitis C virus (HCV) infections. Th1 cytokines such as; interleukin-2 (IL-2), and interferon gamma (IFN-gamma) are necessary for host antiviral immune responses, while Th2 cytokines (IL-4, IL-10) can inhibit the development of these effector mechanisms. OBJECTIVES The aim of the present study was to assess the serum profile of Th1 and Th2 cytokines in treated and non-treated HCV infected individuals. PATIENTS AND METHODS This study was carried out in 63 HCV infected patients (31 under treatment and 32 untreated) and 32 matched HCV-sero negative healthy subjects. Serum samples were checked with an enzyme-linked immune sorbent assay (ELISA) for IL-2, IL-4, IL-10 and IFN-gamma. RESULTS Levels of circulating IL-2, IL-4, IL-10 and IFN-gamma were significantly elevated in HCV patients versus normal controls (2 822.6 ± 1 259.92 vs. 950.8 ± 286.9 pg/mL; 1 987 ± 900.69 vs. 895.91 ± 332.33 pg/mL; 1 688.5 ± 1 405.1 vs. 519.03 ± 177.64 pg/mL and 1 501.9 ± 1 298 vs. 264.66 ± 71.59 pg/mL, respectively; P < 0.001). The serum levels of all cytokines were significantly lower in the patients under treatment than those of the untreated patients (P < 0.001). CONCLUSIONS On the basis of our data, the simultaneous increase of Th1 and Th2 related cytokines may indicate that both Thl and Th2 cytokines are involved in the pathogenesis of HCV infections. Moreover, this activated T-cell response in HCV infected patients may be regulated by treatment.
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Affiliation(s)
- Masoomeh Sofian
- Tuberculosis and Pediatric Infectious Research Center (TPIRC), Arak University of Medical Sciences, Arak, IR Iran
| | - Arezoo Aghakhani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
| | - Ali Asghar Farazi
- Tuberculosis and Pediatric Infectious Research Center (TPIRC), Arak University of Medical Sciences, Arak, IR Iran
| | - Mohammad Banifazl
- Iranian Society for Support of Patients With Infectious Diseases, Tehran, IR Iran
| | - Ali Eslamifar
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
| | - Niloofar Rashidi
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
| | | | - Amitis Ramezani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
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Atsukawa M, Nakatsuka K, Kobayashi T, Shimizu M, Tamura H, Harimoto H, Takahashi H, Sakamoto C. Ribavirin downmodulates inducible costimulator on CD4+ T cells and their interleukin-10 secretion to assist in hepatitis C virus clearance. J Gastroenterol Hepatol 2012; 27:823-31. [PMID: 21871023 DOI: 10.1111/j.1440-1746.2011.06882.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM The immunological mechanism by which ribavirin (RBV) polarizes the T-helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance. METHODS The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4(+) T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed. RESULTS In CD4(+) T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7-H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin-10 (IL-10) released from RBV-stimulated CD4(+) T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL-10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL-10 production by CD4(+) T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination. CONCLUSIONS The downmodulation of ICOS in correlation with a reduction in IL-10 produced by CD4(+) T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.
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Affiliation(s)
- Masanori Atsukawa
- Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Swiątek BJ. Is interleukin-10 gene polymorphism a predictive marker in HCV infection? Cytokine Growth Factor Rev 2012; 23:47-59. [PMID: 22390924 DOI: 10.1016/j.cytogfr.2012.01.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The clinical outcome of hepatitis C virus (HCV) infection varies between individuals - from spontaneous viral clearance and persistence without complication, to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Also patterns of response to interferon-based anti-HCV therapy are different from person to person. This diversity may be affected by host genetic factors, including alterations in genes encoding cytokines. Interleukin-10, as an anti-inflammatory cytokine and immune response modulator, may influence on HCV infection susceptibility as well as spontaneous and treatment-induced HCV eradication. Moreover, it is stated that IL-10 has antifibrotic properties and play a role in progression of liver disease. This review summarized studies on interleukin-10 gene polymorphisms (mainly promoter SNPs at positions -1082(G/A), -819(C/T) and -592(C/A)), which may determine IL-10 production, regarding susceptibility to HCV infection, course of HCV-related liver disease (fibrosis, cirrhosis, hepatocellular carcinoma, ALT abnormalities), spontaneous viral elimination as well as hepatitis C treatment outcomes. Analysis of hereby summarized studies shows that it is difficult to unambiguously determine the importance of IL-10 polymorphism as a predictor of clinical outcome of hepatitis C and response to anti-HCV therapy before its beginning. Thus, future larger studies need to address these issues. Continuation of studies on interleukin-10 polymorphisms as well as identification of other candidate predictive markers in HCV infection has important practical implications and there is a chance that may contribute to reduce the scale of hepatitis C problem.
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Affiliation(s)
- Bogna J Swiątek
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.
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Gao QJ, Liu DW, Zhang SY, Jia M, Wang LM, Wu LH, Wang SY, Tong LX. Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 2009; 15:5610-9. [PMID: 19938203 PMCID: PMC2785066 DOI: 10.3748/wjg.15.5610] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the relationship between the polymorphisms in some cytokines and the outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.
METHODS: Samples were obtained from 203 patients infected with HBV and/or HCV while donating plasma in 1987, and 74 controls were obtained from a rural area of North China. Antibodies to HBV or HCV antigens were detected by enzyme-linked immunoassay. The presence of viral particles in the serum was determined by nested reverse-transcriptase polymerase chain reaction (PCR). Hepatocellular injury, as revealed by alanine aminotransferase (ALT) and aspartate aminotransferase level, was detected by a Beckman LX-20 analyzer. DNA was extracted from blood cells. Then, the single nucleotide polymorphisms of IL-2-330, IFN-γ+874, IL-10-1082/-592 and IL-4-589 were investigated by restriction fragment length polymorphism-PCR or sequence specific primer-PCR.
RESULTS: Persistent infection with HBV, HCV, and HBV/HCV coinfection was associated with IL-2-330 TT genotype and T allele, IFN-γ+874 AA genotype, and IL-10-1082 AA genotype. The clinical outcome of HBV and/or HCV infection was associated with IL-2-330 TT genotype and T allele, IFN-γ+874 AA genotype, and IL-10-1082 AA genotype. IL-2-330 GG genotype frequency showed a negative correlation with clinical progression, IL-10-1082 AA genotype frequency showed a positive correlation and IL-10-1082 AG genotype frequency showed a negative correlation with clinical progression. HCV RNA positive expression was associated with IL-10-1082 AA genotype and the A allele frequency. Abnormal serum ALT level was associated with IL-10-592 AC genotype frequency and IL-4-589 CC genotype, CT genotype, and the C allele.
CONCLUSION: These results suggest that polymorphisms in some cytokine genes influence persistent HBV and HCV infection, clinical outcome, HCV replication, and liver damage.
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Dai CY, Chuang WL, Lee LP, Pan WC, Huang JF, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Yu ML. Association between transforming growth factor-beta 1 polymorphism and virologic characteristics of chronic hepatitis C. Transl Res 2008; 152:151-156. [PMID: 18940717 DOI: 10.1016/j.trsl.2008.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2008] [Revised: 08/02/2008] [Accepted: 08/12/2008] [Indexed: 01/22/2023]
Abstract
The production of transforming growth factor beta 1 (TGF-beta1) has been reported as being significantly associated with the gene polymorphism in the leader sequence at positions +29. The current study aimed to evaluate the associations between the polymorphism and the clinical characteristics of chronic hepatitis C (CHC). A total of 422 (252 men; mean age: 49.7 +/- 11.2 years) Taiwanese CHC patients with liver biopsies were enrolled. The TGF-beta1 gene polymorphism at position +29 (T or C), hepatitis C virus (HCV) RNA genotypes, and serum HCV RNA levels of these patients were determined. Of the 422 patients, the frequency of the T allele was 45.4%. Based on univariate analyses, a significantly lesser proportion of patients with allele T had high viral loads than those who were without allele T (P = 0.026). The lesser HCV RNA levels and HCV genotype 1b infection were significantly associated with the inheritance of the T allele in female patients based on univariate (P = 0.012 and 0.007, respectively) and multivariate regression (odds ratio/95% confidence interval: 0.434/0.219-0.859 and 0.468/0.237-0.927, respectively) analyses. In male patients with or without inheritance of the T allele, the clinical characteristics were similar. In conclusion, the association between TGF-beta1 polymorphism and virologic characteristics of chronic HCV infection implicated a significant role of host genetic factors on the clinical features of CHC. Female patients who carry T allele at position +29 were predisposed to be associated with HCV genotype non-1b infection and lesser HCV viral load, which revealed the gender effect.
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Affiliation(s)
- Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, the Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Byrnes AA, Li DY, Park K, Thompson D, Mocilnikar C, Mohan P, Molleston JP, Narkewicz M, Zhou H, Wolf SF, Schwarz KB, Karp CL. Modulation of the IL-12/IFN-γ axis by IFN-α therapy for hepatitis C. J Leukoc Biol 2006; 81:825-34. [PMID: 17148690 DOI: 10.1189/jlb.1006622] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
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Affiliation(s)
- Adriana A Byrnes
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Dai CY, Chuang WL, Lee LP, Chen SC, Hou NJ, Lin ZY, Hsieh MY, Hsieh MY, Wang LY, Chang WY, Yu ML. Associations of tumour necrosis factor alpha promoter polymorphisms at position -308 and -238 with clinical characteristics of chronic hepatitis C. J Viral Hepat 2006; 13:770-774. [PMID: 17052277 DOI: 10.1111/j.1365-2893.2006.00767.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate the association between G vs A transitions in the promoter region of the tumour necrosis factor (TNF) alpha at positions -308 (TNF308.2) and -238 (TNF238.2) and clinical features of chronic hepatitis C (CHC). These two promoter TNF-alpha variants were determined in 250 biopsy-proven CHC patients by polymerase chain reaction amplification, followed by the Restriction Fragment Length Polymorphism (RFLP) method. The distribution of -308 and -238 TNF-alpha promoter genotypes were TNF308.1/TNF308.1: 187 (74.8%), TNF308.1/TNF308.2: 57 (22.8%) and TNF308.2/TNF308.2: 6 (2.4%), respectively, and TNF238.1/TNF238.1: 247 (98.8%) and TNF238.1/TNF238.2: 3 (1.2%). The frequencies of the TNF308.2 and TNF238.2 promoter alleles were 13.8% and 0.6%. Increased TNF308.2 allele copy numbers were significantly associated with increased frequency of lower pretreatment hepatitis C virus (HCV) RNA levels (<800 000 IU/mL; P = 0.031) and severe fibrosis stage (F3-F4; P = 0.006) and higher mean fibrosis score (P = 0.007). The higher cytokine production (with one or two TNF308.2 alleles) was correlated significantly with lower pretreatment HCV RNA levels with a lower mean HCV RNA level (P = 0.024) and increased frequency of lower pretreatment HCV RNA levels (<800 000 IU/mL; P = 0.017). Stepwise logistic regression showed that higher fibrosis score and low HCV RNA levels were independently related to the TNF308.2 allele [odds ratio (95% CI): 1.385 (1.127-1.702) and 0.698 (0.488-0.990)]. We conclude that inheritance of the TNF-alpha promoter genotype at the position -308 appears to be associated with variability in severity of fibrosis and viral load in chronic HCV infection.
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Affiliation(s)
- C-Y Dai
- Division of Hepatobiliary, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, No. 100 Tzyou 1st Road, Kaohsiung 807, Taiwan
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Akyüz F, Polat N, Kaymakoglu S, Aksoy N, Demir K, Beşişik F, Badur S, Cakaloglu Y, Okten A. Intrahepatic and peripheral T-cell responses in genotype 1b hepatitis C virus-infected patients with persistently normal and elevated aminotransferase levels. World J Gastroenterol 2006; 11:7188-91. [PMID: 16437670 PMCID: PMC4723403 DOI: 10.3748/wjg.v11.i45.7188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate whether the cytokine responses in liver and serum differ in chronic hepatitis C patients with normal and high alanine aminotransferase (ALT) levels. METHODS Thirty-three (16 with normal ALT level as group 1 and 17 with elevated ALT level as group 2) patients infected with genotype 1b hepatitis C virus (HCV) were examined. Liver infiltrating lymphomononuclear cells (LILMCs) were isolated from liver biopsy by collagenase type 1 and stimulated with phytohemagglutinin and interleukin 2 (IL-2). IL-10, IL-12, interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) were determined in serum and LILMCs by ELISA. RESULTS Serum cytokine levels were similar in both groups (P>0.05). Stimulated IFN-gamma and TNF-alpha levels in LILMCs were increased in both groups. IL-12 and IL-10 levels stimulated with IL-2 were higher in group 1 than in group 2 (P = 0.023). Histological activity index (HAI) and stage had a negative correlation with TNF-alpha and IFN-gamma levels in group 2. CONCLUSION Increased T-helper type 2 (Th2) cytokine response may regress inflammatory and biochemical activity. Progression of histological abnormalities in persons with elevated ALT probably depends on insufficient Th2 cytokine response, which does not balance Th1 cytokine response.
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Affiliation(s)
- Filiz Akyüz
- Department of Gastroenterohepatology, Istanbul University, Istanbul, Turkey.
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12
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Tortorella C, Napoli N, Panella E, Antonaci A, Gentile A, Antonaci S. Asymptomatic systemic sarcoidosis arising 5 years after IFN-alpha treatment for chronic hepatitis C: a new challenge for clinicians. J Interferon Cytokine Res 2005; 24:655-8. [PMID: 15684818 DOI: 10.1089/jir.2004.24.655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Interferon (IFN)-induced sarcoidosis is well documented. Herein, we report the case of a patient with chronic hepatitis C (CHC) who developed IFN-alpha-induced sarcoidosis. The clinical features of this case make it unique among all cases so far described. The patient was, in fact, asymptomatic for sarcoidosis, and the disease, characterized by liver and lung granulomatosis, was discovered by chance during the CHC follow-up. The diagnosis was made 5 years after IFN-alpha discontinuation. A pathogenetic role for IFN-alpha in our patient is supported by a liver biopsy performed before the therapy with IFN-alpha was started, showing no evidence of granulomatous localizations. This case suggests that the incidence of sarcoidosis during IFN-alpha treatment is underestimated. A search for clinical and laboratory findings typical of the disease, as well as a liver biopsy, should always be included in the follow-up of CHC patients undergoing therapy with IFN-alpha.
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Affiliation(s)
- Cosimo Tortorella
- Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Bari, Italy.
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FUJIOKA N, TANAKA T, ARIYASU T, YANAI Y, YAMAMOTO S, YAMAUCHI H, IKEGAMI H, IKEDA M, ORITA K, KURIMOTO M. In vitro effects of interferon-alpha subtypes on the Th1/Th2 balance in the peripheral blood mononuclear cells from patients with hepatitis C virus infection. Biomed Res 2004. [DOI: 10.2220/biomedres.25.75] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Schvoerer E, Navas MC, Thumann C, Fuchs A, Meyer N, Habersetzer F, Stoll-Keller F. Production of interleukin-18 and interleukin-12 in patients suffering from chronic hepatitis C virus infection before antiviral therapy. J Med Virol 2003; 70:588-93. [PMID: 12794721 DOI: 10.1002/jmv.10434] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interleukin-12 and -18 (IL-12 and IL-18) are known to enhance the cytotoxic T-lymphocyte response synergistically, but their precise involvement in hepatitis C virus (HCV) infection is not well known, especially for IL-18. Enzyme-linked immunosorbent assay (ELISA) was used to study the production of these cytokines in plasma and peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) of patients infected chronically with HCV before initiation of antiviral therapy. Fifty-six patients and 40 healthy controls were evaluated. Patients infected with genotype 1 or with genotype other than genotype 1 HCV had significantly a high production of plasma IL-12 compared with controls (P < 0.05). However, patients infected with genotype 1 HCV had lower levels of PBMC IL-18 than were founded in the controls (P < 0.05); plasma IL-18 also tended to be lower in this group of patients than in the controls, although nonsignificantly. Plasma IL-18 was related to hepatic histological activity (P < 0.05). The data suggest a relationship between these two cytokines and some features of HCV infection, so that their respective production in relation to the outcome of the infection deserves further study.
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Affiliation(s)
- E Schvoerer
- Institut de Virologie et Unité INSERM 544, Université Louis Pasteur, Strasbourg, France.
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Glas J, Török HP, Simperl C, König A, Martin K, Schmidt F, Schaefer M, Schiemann U, Folwaczny C. The Delta 32 mutation of the chemokine-receptor 5 gene neither is correlated with chronic hepatitis C nor does it predict response to therapy with interferon-alpha and ribavirin. Clin Immunol 2003; 108:46-50. [PMID: 12865070 DOI: 10.1016/s1521-6616(03)00059-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Unlike in HIV, homozygosity for a 32-bp deletion (Delta 32) of the chemokine receptor 5 (CCR5) gene was recently described in increased frequency in patients with chronic hepatitis C (HCV). Thus, it was speculated that this mutation might be relevant for disease susceptibility and influence the response to antiviral therapy. The present study sought to confirm the association between HCV and the Delta 32 mutation of the CCR5 gene and to correlate it with the response to therapy with interferon-alpha-2a and ribavirin. Sixty-two patients with HCV and 119 healthy unrelated controls were genotyped for the Delta 32 mutation. For the correlation between the Delta 32 mutation and response to therapy, only patients (n = 59) who completed 6 months of combination therapy as part of a prospective study were evaluated. The Delta 32 mutation was not observed in increased frequency in HCV. Furthermore, a significant difference of the HCV load or aminotransferase concentrations was not observed in carriers versus noncarriers of the Delta 32 mutation. After stratification for potentially confounding factors such as gender or HCV genotype, a significant difference was also not detected with respect to treatment outcome. These observations argue strongly against a role of CCR5 for susceptibility to HCV infection or response to combination therapy.
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Affiliation(s)
- J Glas
- Medizinische Klinik, Klinikum der Ludwig-Maximilians Universität München, Standort Innenstadt, Munich, Germany
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16
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Woitas RP, Ahlenstiel G, Iwan A, Rockstroh JK, Brackmann HH, Kupfer B, Matz B, Offergeld R, Sauerbruch T, Spengler U. Frequency of the HIV-protective CC chemokine receptor 5-Delta32/Delta32 genotype is increased in hepatitis C. Gastroenterology 2002; 122:1721-8. [PMID: 12055576 DOI: 10.1053/gast.2002.33660] [Citation(s) in RCA: 89] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND & AIMS A homozygous 32-base pair deletion in the CCR5 gene (CCR5-Delta32) protects against human immunodeficiency virus infection (HIV). However, the role of this mutation in other infections, such as hepatitis C virus (HCV) infection, has not been defined. METHODS We determined the frequency of the CCR5-Delta32 mutation by polymerase chain reaction in anti-HCV(+) (n = 153), anti-HIV(+) (n = 102), and anti-HCV(+)/HIV(+) (n = 130) white patients as well as in 102 healthy blood donors. Then, HIV and HCV loads, aminotransferases, and CD4 and CD8 cell counts were compared between the resulting subsets of CCR5-Delta32/wild-type heterozygotes, CCR5-Delta32, and wild-type homozygotes, respectively. RESULTS Twelve of 153 (7.8%) anti-HCV-seropositive patients and 1 of 102 (1.0%) healthy blood donors were CCR5-Delta32 homozygous, whereas CCR5-Delta32 homozygosity was absent in anti-HIV(+) and anti-HCV(+)/HIV(+) patients (P < 0.001). The frequency of the CCR5-Delta32 allele was higher in the anti-HCV(+) (16.0%, P < 0.05) and anti-HCV(+)/HIV(+) (12.7%, NS) patients than in healthy blood donors (8.3%) and anti-HIV(+) patients (9.3%), respectively. Anti-HCV(+) CCR5-Delta32 homozygotes occurred 3 times more frequently than expected from the Hardy-Weinberg equation (P < 0.0001) and had significantly higher HCV loads than wild-type patients (P = 0.045). CONCLUSIONS The increased prevalence of CCR5-Delta32 homozygosity associated with increased viral loads in patients with chronic hepatitis C suggests that the CCR5-Delta32 mutation may be an adverse host factor in hepatitis C.
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Affiliation(s)
- Rainer P Woitas
- Department of Internal Medicine I, University of Bonn, Bonn, Germany.
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Woitas RP, Petersen U, Moshage D, Brackmann HH, Matz B, Sauerbruch T, Spengler U. HCV-specific cytokine induction in monocytes of patients with different outcomes of hepatitis C. World J Gastroenterol 2002; 8:562-6. [PMID: 12046093 PMCID: PMC4656444 DOI: 10.3748/wjg.v8.i3.562] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2002] [Revised: 04/13/2002] [Accepted: 04/25/2002] [Indexed: 02/06/2023] Open
Abstract
AIM Cytokine release by macrophages critically determines the type of immune response to an antigen. Therefore, we studied hepatitis C virus (HCV)-specific induction of interleukins-1 beta, -10, -12 (IL-1 beta, IL-10, IL-12), and tumor necrosis factor-alpha (TNF-alpha) in monocytes. METHODS Intracellular cytokine expression was studied by flow cytometry in 23 patients with chronic hepatitis C, 14 anti-HCV seropositives without viremia and 11 controls after stimulation of peripheral blood mononuclear cells with recombinant core, NS3, NS4, NS5a and NS5b proteins. RESULTS Patients with HCV viremia revealed greater spontaneous expression of IL-1beta, TNF-alpha, and IL-10. Furthermore, greater than twofold higher IL-10 expression was induced by the HCV antigens in chronic hepatitis C than in the other two groups (P<0.05). In contrast, neither IL-12 nor TNF-alpha was induced preferentially. CONCLUSION In chronic hepatitis C antigen-specific cytokine induction in monocytes is apparently shifted towards predominant IL-10 induction - not counterbalanced by antiviral type 1 cytokines. This may contribute to persistent viral replication.
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Affiliation(s)
- Rainer P Woitas
- Department of Internal Medicine I, University of Bonn, D-53105 Bonn, Germany.
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Vidigal PG, Germer JJ, Zein NN. Polymorphisms in the interleukin-10, tumor necrosis factor-alpha, and transforming growth factor-beta1 genes in chronic hepatitis C patients treated with interferon and ribavirin. J Hepatol 2002; 36:271-7. [PMID: 11830340 DOI: 10.1016/s0168-8278(01)00243-4] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS In hepatitis C infection, the production of inappropriate cytokine levels appears to contribute to viral persistence and to affect the response to antiviral therapy. Additionally, polymorphisms in the cytokine genes may affect the production of the cytokines. In this study, we determined the frequency of the genotypes associated with polymorphisms of the interleukin-10 and tumor necrosis factor-alpha gene promoters, and transforming growth factor-beta 1 gene leader sequence, and investigated their association with clinical features and the response to interferon-alpha and ribavirin therapy in chronic hepatitis C infection. METHODS Genomic DNA from 80 patients and 37 racially matched healthy controls was studied by polymerase chain reaction and direct automated sequencing. RESULTS The interleukin-10 -1082 G/G genotype was identified more frequently in patients than in controls (P=0.048). The transforming-growth factor-beta 1 +29 (codon 10) C/C genotype was associated with resistance to the therapy (P=0.029). After adjusting for potential confounding variables, patients exhibiting the C/C genotype were less likely to respond to treatment than patients with the T/T or T/C genotypes. CONCLUSIONS These results suggest that inheritance of the interleukin-10 -1082 G/G and the transforming growth factor-beta 1 +29 C/C genotypes, which appear to affect the cytokine production, may be associated with susceptibility to chronic hepatitis C infection and resistance to combined antiviral therapy.
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Affiliation(s)
- Pedro G Vidigal
- Division of Gastroenterology, Hepatology and Internal Medicine. Mayo Clinic and Mayo Foundation, Rochester, MN, USA
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Piazzolla G, Tortorella C, Fiore G, Fanelli M, Pisconti A, Antonaci S. Interleukin-12 p40/p70 ratio and in vivo responsiveness to IFN-alpha treatment in chronic hepatitis C. J Interferon Cytokine Res 2001; 21:453-61. [PMID: 11506737 DOI: 10.1089/10799900152434303] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
To evaluate the relationship between cytokine balance and responsiveness to interferon-alpha (IFN-alpha), we investigated the production of IFN-gamma, interleukin-10 (IL-10), IL-12 p70, and IL-12 p40 by peripheral blood mononuclear cell (PBMC) cultures from patients with chronic hepatitis C (CHC) before and after 1 year of IFN-alpha treatment. Before the therapy, responder (R) patients exhibited lower IFN-gamma release, higher IL-10 production, and higher values of the IL12 p40/p70 ratio compared with nonresponders (NR). Increased sensitivity to the effects of IL-12 and IL-10, as well as higher IL-12-dependent IFN-gamma secretion, were also found in the R subset. After IFN-alpha therapy, an increase in IFN-gamma production and a decrease in the IL-12 p40/p70 ratio were observed in R patients, whereas opposite results were obtained in the NR group. Finally, the therapy induced downregulation of IL-10 production and cell responsiveness to recombinant IL-12 in all patients. These findings imply that predominance of a T helper 2 (Th2) cytokine profile in CHC patients favors the beneficial effects of IFN-alpha, thus suggesting a therapeutic role for Th1-driven stimulation of immune response. The findings also stress the primary importance of the IL-12 p40 and p70 balance in the modulation of immune responses to hepatitis C virus (HCV).
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Affiliation(s)
- G Piazzolla
- Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Bari, Italy.
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Sarih M, Bouchrit N, Benslimane A. Different cytokine profiles of peripheral blood mononuclear cells from patients with persistent and self-limited hepatitis C virus infection. Immunol Lett 2000; 74:117-20. [PMID: 10996386 DOI: 10.1016/s0165-2478(00)00210-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
An imbalance between T helper cell Th1 and Th2 like cytokines has been described in several chronic infectious diseases. In an attempt to characterise the mechanism responsible for viral persistence in hepatitis C virus (HCV)-related chronic infection, we analyzed Th1 cytokines (IL-2, IL-12, IFN-gamma) and Th2 cytokines (IL-4, IL-10) production by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) derived from ten patients with viremic chronic hepatitis C, five healthy HCV seropositive individuals and four HCV seronegative individuals. Cytokine production was determined by enzyme-linked immunosorbent assay (ELISA) after 72 h of stimulation. The results showed that the production of IFN-gamma by PHA-stimulated PBMC was decreased in patients with hepatitis C infection (P=0.05). IL-4 production was not detected in both patients and controls, while no difference was observed for IL-2, IL-10 and IL-12 production between patients and controls. Furthermore, IL-12 and IFN-gamma production was weaker in patients with viremic chronic hepatitis C than in subjects who were able to clear the virus (P=0.01; P=0.03, respectively). These results clearly indicate that a defect both in IL-12 and IFN-gamma production may contribute to the persistence of HCV infection.
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Affiliation(s)
- M Sarih
- Immunology Center, Medical School and Pasteur Institute of Morocco, Morocco.
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Piazzolla G, Tortorella C, Schiraldi O, Antonaci S. Relationship between interferon-gamma, interleukin-10, and interleukin-12 production in chronic hepatitis C and in vitro effects of interferon-alpha. J Clin Immunol 2000; 20:54-61. [PMID: 10798608 DOI: 10.1023/a:1006694627907] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
In the current study, increased interferon (IFN)-gamma, interleukin (IL)-10, and IL-12 p40 serum levels were observed in patients with chronic hepatitis C (CHC) compared to controls. Patients also displayed an increased spontaneous IFN-gamma release but a deficient peripheral blood mononuclear cells (PBMC) IFN-gamma production following stimulation with Staphylococcus aureus Cowan I strain (SAC). No difference was found with reference to spontaneous or phytohaemagglutinin (PHA)-induced IL-10 release between patients and controls, whereas a higher IL-12 p70 and IL-12 p40 secretion triggered by SAC was observed in patients. Moreover, IL-12 p40/p70 ratio following SAC stimulation was higher in patients compared to controls and a negative correlation was found between this ratio and IFN-gamma amounts. Recombinant IL-12 (rIL-12) as well as neutralizing anti-IL-10 monoclonal antibodies (mAbs) were able to restore the compromised IFN-gamma production. Of note, anti-IL-10 supplementation induced a lower IL-12 p40/p70 ratio in HCV subjects as compared to controls. Finally, IFN-alpha upregulated in vitro IFN-gamma, IL-10, and IL-12 p70 release but not IL-12 p40 secretion, this giving rise to a normalization of IL-12 p40/p70 ratio. The data suggest the occurrence of an enhanced responsiveness to IL-10 modulating effects, likely mediated by an imbalance of IL-12 p40/p70 ratio, in chronic HCV infection. Cytokine balance restoration might thus contribute to achieve therapeutical results in chronic hepatitis C.
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Affiliation(s)
- G Piazzolla
- Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari Medical School, Italy.
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Lechmann M, Woitas RP, Langhans B, Kaiser R, Ihlenfeldt HG, Jung G, Sauerbruch T, Spengler U. Decreased frequency of HCV core-specific peripheral blood mononuclear cells with type 1 cytokine secretion in chronic hepatitis C. J Hepatol 1999; 31:971-8. [PMID: 10604568 DOI: 10.1016/s0168-8278(99)80307-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND/AIM Since the outcome of hepatitis C infection appears to be correlated with the immune response to the HCV core protein, the aim of this study was to investigate the T cell response to hepatitis C virus core and core-derived antigens. METHODS As this response may be regulated importantly by differential secretion of cytokines, we determined the number of peripheral blood mononuclear cells (PBMC) that secreted IL-2, IL-4, IL-10, and IFN-gamma in response to a recombinant HCV core protein and a panel of 19 core-derived peptides, using the ELI-Spot-technique. Two groups of patients were studied: group A: 11 patients with previously self-limited HCV infection; group B: 12 patients with chronic hepatitis C. RESULTS In group B significantly less IFN-gamma spot forming cells (SFC) could be detected, both after stimulation with the core protein (0.083+/-0.083 SFC vs. 1.3+/-0.4 SFC/10(5) PBMC; p = 0.005 and with the core-derived peptides (1.3+/-0.5 vs. 4.4+/-1.1 SFC SFC/10(5) PBMC; p = 0.007). By analyzing the cytokine response to each single peptide, we found IFN-gamma responses to peptides aa 39-63 and aa 148-172 in group A but not in group B (p<0.03). In group B also, fewer IL-2 secreting cells were found after peptide stimulation (p = 0.04). Whereas subjects of group B showed IL-10-specific responses to HCV peptides more frequently than patients with self-limiting hepatitis C (p = 0.03), the number of IL-4-producing cells was not different between the two groups. CONCLUSIONS The data suggest that patients with persistent viremia and chronic liver disease (group B) have less PBMC showing type 1 cytokine (IL-2, IFN-gamma) responses to HCV core protein than patients with self-limited HCV infection (group A).
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Affiliation(s)
- M Lechmann
- Department of Internal Medicine, University of Bonn, Germany
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